The historical pathology of the brain in Alzheimer's disease (AD) is characterized by the amyloid cascade hypothesis, in which amyloid β protein accumulates in the extracellular parenchyma as senile plaque and triggers phosphorylation of microtubule-associated protein tau for forming neurofibrillary tangle in the human neurons. Whether these protein existences differed in the brain parenchyma, the relationship of these proteins of accumulation mechanisms is unknown. In the case of brain pathological analysis, the level of phosphorylation for tau has been decreased in the paraffin-embedded sections compared with biochemical analysis. Here, we have established and developed a method to highlight phosphorylated proteins including tau with frozen sections, as the HIGh Affinity Staining Histological Immunoreactivity (HIGASHI) method. Using this HIGASHI method, hyper-phosphorylated tau could be detected in the mossy fiber on the frozen brain sections of wild-type mice under hypothermia conditions. Here, we attempted the HIGASHI method to detect senile plaque and phosphorylated tau in the AD model mouse brains. Phosphorylated tau was found in the center of senile plaques in the mice brain parenchyma. Additionally, these senile plaques colocalized with microglia cells in the center of senile plaques. Interestingly, senile plaques have been made in the tau knock-out mice brains expressing human amyloid precursor protein. Thus, senile plaques have been composed of Aβ and phosphorylated tau in the brain, but tau isn't necessary for bearing senile plaques.

Alzheimer's disease (AD) is the most common tauopathy characterized by progressive accumulation of Aß and tau neuropathology. Tau is expressed in two major isoforms containing either 3 or 4C-terminal repeats, 3R and 4R. Despite tau isoforms occurring in roughly equimolar ratios in AD, the majority of research focus in developed mouse and in vitro models focus only on 4Rtau. To generate a more complete model of AD tauopathy and understand specific tau isoform-mediated neuropathology and neurodegeneration, we generated a transgenic mouse line expressing both 3Rtau and 4Rtau and determined how this impacted the timing and severity of neuropathological and behavioral changes.

3Rtau-tg and 4Rtau-tg mice were crossed to generate 3R/4Rtau-tg bigenic mice. At 3, 6, and 9 months of age, mice were assessed for behavior, neuropathology and RNA expression.

3R/4Rtau bigenic mice expressed increased tau and phosphorylated tau in the hippocampus and cortex compared to single (3R or 4R) transgenic cohorts as early as 3-months of age and this was accompanied with increased astrogliosis and microglial activation. Bigenic mice had significantly greater behavioral deficits compared to either single transgenic littermates in spatial learning and memory as well as nest building, indicative of depression and/or cognitive deficits.

This new mouse model of tauopathy more completely recapitulates the pattern, severity and accumulation of tau and associated neuropathology and behavioral changes observed in human tauopathies such as AD. 3R/4Rtau-tg bigenic mice should supplant existing single transgenic tau models for general validation of therapeutic targets and investigations of novel therapies on tauopathy endpoints.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. There are over 10 million new cases of AD each year worldwide, implying one new case every 3.2 seconds. Post-translational modifications (PTMs) such as phosphorylation, glycosylation, and citrullination have emerged as key modulators of protein function in AD, influencing protein aggregation, clearance, and toxicity. Mass spectrometry (MS) has become an indispensable tool for detecting and quantifying these PTMs, offering valuable insights into their role in AD pathogenesis. This review explores recent advancements in MS-based studies of PTMs in AD, with emphasis on MS techniques like data-dependent acquisition (DDA) and data-independent acquisition (DIA), as well as enrichment methods used to characterize PTMs. The applications of these MS-based approaches to the study of various PTMs are highlighted, which have significantly accelerated the biomarker discovery process, providing new avenues for early diagnosis and therapeutic targeting. Advances in biological understanding and analytical techniques, while addressing the challenges and future directions, will be discussed.

Tau is a microtubule-associated protein (MAP) and is critical for maintaining the cytoskeleton of neurons. Tau and its post-translational modifications (PTMs) have been studied for decades, yet the exact composition of intact tau and its truncation products present in the human brain has evaded study at the proteoform level. Here, we show that tau proteoform profiling and exact characterization are possible using immunoprecipitation (IP) and the new approach of individual ion mass spectrometry (I2MS). We provide a first glimpse of the tau proteoform landscape present in the CHAPS-soluble extracts from the temporal cortex of a control subject and a donor with Alzheimer's disease (AD). Profiling and identification of four isoforms (0N3R, 1N3R, 0N4R, and 1N4R), truncated products (e.g., 72-172 derived from the 0N3R/0N4R isoforms), and intact tau proteoforms harboring PTMs include phosphorylation, methylation, and acetylation. The specific tau proteoform identification typically employs proton transfer charge reduction (PTCR) and electron transfer dissociation (ETD) with spectral readout by individual ion tandem mass spectrometry (I2MS2). A precise understanding of the tau proteoform landscape over the course of neurodegeneration is critical to understand AD pathology vs related dementias. The assay approach reported here will advance AD research, gives a sense of what is technologically possible for new biomarker discovery and will assist the development of therapeutics using the most exact kind of compositional information on tau.

Tau hyperphosphorylation represents a critical pathological hallmark of Alzheimer's disease (AD), a prevalent neurodegenerative disorder characterized by progressive cognitive decline. The ubiquitin-specific proteases 14 (USP14) impairs proteasomal function and accelerates hyperphosphorylated Tau accumulation, making it an attractive therapeutic target for modulating the ubiquitin-proteasome pathway in AD treatment. In this study, it is reported that wogonoside-functionalized ultrasmall Cu2-xSe nanoparticles (CSPW NPs) significantly reduce hyperphosphorylated Tau accumulation and alleviate AD symptoms. The therapeutic mechanism involves activation of the ubiquitin-proteasome pathway through USP14 inhibition by CSPW NPs, thereby preventing hyperphosphorylated Tau accumulation. Furthermore, after cell membrane coating (CSPW@CM NPs), these nanoparticles efficiently cross the blood-brain barrier with focused ultrasound assistance and accumulate in the brain to target neurons. Within neurons, they inhibit USP14, reduce phosphorylated Tau deposition, enhance microtubule stability, mitigate synaptic loss, restore synaptic integrity, and ultimately alleviate cognitive dysfunction in AD mice. The findings highlight the substantial potential of USP14 modulation for mitigating Tau hyperphosphorylation in the treatment of AD and related tauopathies.

Tau phosphorylation is a tightly regulated process that ensures proper neuronal function. Indeed, hyperphosphorylation of tau closely contributes to neuronal dysfunction leading to neurodegenerative diseases, including tauopathies, which are characterized by excessive and aberrant tau phosphorylation and cognitive decline. Therefore, it is important to understand how to regulate its phosphorylation. In this regard, the protein tyrosine phosphatase receptor delta (PTPRD) has been genetically implicated in tau pathology in humans, but the mechanisms underlying its role in tau regulation remain unclear. This study investigates the impact of Ptprd deficiency on tau phosphorylation, cognitive function, neuroinflammation, and synaptic markers in aging mice.

Mice lacking Ptprd showed increased tau phosphorylation at multiple sites associated with its pathological aggregation. This effect was accompanied by the activation of the tau-related kinase Abl1, particularly in the hippocampus. Behavioral assessments revealed significant impairments in learning and memory, demonstrating the functional impact of these alterations. Moreover, Ptprd knockout mice showed increased microgliosis in both the entorhinal cortex and the hippocampus, suggesting a pro-inflammatory response. Furthermore, the synaptic protein PSD95 was also reduced in the cortex, indicating potential synaptic dysfunction.

The loss of Ptprd leads to increased tau phosphorylation, cognitive impairments, microgliosis, and synaptic alterations in older mice. Our findings also suggest that Ptprd plays a critical role in maintaining tau homeostasis through the Abl1 kinase. This indicates a new potential therapeutic approach for tauopathies, where PTPRD could serve a protective role against tau-related pathologies and may act as a key modulator in disease progression.

Bisphenol A (BPA) is an endocrine-disrupting compound linked to impairments in motor function and the manifestation of anxiety-like behaviors. The present study investigated the effects of carnosic acid (CA) on BPA-induced motor deficits and explored the role of parkin in the autophagic mechanism. First, C57BL/6 J male mice were orally administered with CA (5 mg/kg and 20 mg/kg) or RE (80 mg/kg rosemary extract) to test the motor function and anxiety-like behaviors in BPA (50 μg/kg) treatment. The results showed that CA and RE ameliorate BPA-induced motor impairments and anxiety-like behaviors. Moreover, CA and RE attenuated BPA-induced phosphorylation of tau and α-synuclein while restoring the expression levels of autophagy-related proteins, including parkin, PINK1, PI3K, Atg7, Beclin1, and LC3B-II. Then, SH-SY5Y cells were treated with 20 nM BPA and 1 μM CA or 0.5 μg/mL RE for 18 h. The results showed that treatment of CA and RE with BPA activated the parkin pathway and reduced the levels of Ser396p-tau and p-α-synuclein. Moreover, treatment of CA or RE with BPA restored the parkin signaling, resulting in the upregulation of autophagy-related proteins. However, wortmannin treatment attenuated this restorative effect of CA or RE. Additionally, transfection with parkin siRNA in cells reversed the ability of CA or RE to counteract BPA-induced reductions in autophagy-related proteins and increased the accumulation of misfolded proteins. Therefore, the results indicated that CA and RE improved motor impairments and reduced the accumulation of misfolding proteins induced by BPA, potentially through regulating autophagy by parkin.

Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia, contributing to around 60-80% of cases. The main pathophysiology of AD is characterized by an abnormal accumulation of protein aggregates extracellularly (beta-amyloid plaques) and intracellularly (neurofibrillary tangles of hyperphosphorylated tau). However, an increasing number of studies have also suggested neuroinflammation may have a crucial role in precipitating the cascade reactions that result in the development of AD neuropathology. In particular, several studies indicate microRNAs (miRNAs) can act as regulatory factors for neuroinflammation in AD, with potential to affect the occurrence and/or progression of AD inflammation by targeting the expression of multiple genes. Therefore, miRNAs may have potential as therapeutic targets for AD, which requires more research. This article will review the existing studies on miRNAs that have been identified to regulate neuroinflammation, aiming to gain further insights into the specific regulatory processes of miRNAs, highlight the diagnostic and therapeutic potential of miRNAs as biomarkers in AD, as well as current challenges, and suggest the further work to bridge the gap in knowledge to utilize miRNAs as therapeutic targets for AD.

Alzheimer's disease (AD) is regarded as a neurodegenerative disease, and it has been proposed that AD may be a systemic disease. Studies have reported associations between non-neurological diseases and AD. The correlations between AD pathology and systemic (non-neurological) pathological changes are intricate, and the mechanisms underlying these correlations and their causality are unclear. In this article, we review the association between AD and disorders of other systems. In addition, we summarize the possible mechanisms associated with AD and disorders of other systems, mainly from the perspective of AD pathology. Regarding the relationship between AD and systemic pathological changes, we aim to provide a new outlook on the early warning signs and treatment of AD, such as establishing a diagnostic and screening system based on more accessible peripheral samples.

How the human brain develops and what goes awry in neurological disorders represent two long-lasting questions in neuroscience. Owing to the limited access to primary human brain tissue, insights into these questions have been largely gained through animal models. However, there are fundamental differences between developing mouse and human brain, and neural organoids derived from human pluripotent stem cells (hPSCs) have recently emerged as a robust experimental system that mimics self-organizing and multicellular features of early human brain development. Controlled integration of multiple organoids into assembloids has begun to unravel principles of cell-cell interactions. Moreover, patient-derived or genetically engineered hPSCs provide opportunities to investigate phenotypic correlates of neurodevelopmental disorders and to develop therapeutic hypotheses. Here, we outline the advances in technologies that facilitate studies by using assembloids and summarize their applications in brain development and disease modeling. Lastly, we discuss the major roadblocks of the current system and potential solutions.

Phosphorylation plays a crucial role in both normal and disease processes involving the microtubule-associated protein tau. Physiologically, phosphorylation regulates tau's subcellular localization within neurons and is involved in fetal development and animal hibernation. However, abnormal phosphorylation of tau is linked to the formation of neurofibrillary tangles (NFTs) in various human tauopathies. Interestingly, the patterns of tau phosphorylation are similar in both normal and abnormal processes, leaving unclear whether phosphorylated tau retains its functional role in normal processes. The relationship between tau phosphorylation and NFT assembly in tauopathies is also still debated. To address these questions, we investigated the effects of tau phosphorylation on microtubule binding, cooperative protein envelope formation, and NFT filament assembly relevant to tauopathies. Consistent with previous results, our findings show that tau phosphorylation decreases tau's overall affinity for microtubules, but we reveal that phosphorylation more dramatically impacts the cooperativity between tau molecules during tau envelope formation along microtubules. Additionally, we observed that the specific pattern of phosphorylation, rather than overall phosphorylation level, strongly impacts the assembly of tau filaments in vitro. Our results reveal new insights into how tau phosphorylation impacts tau's physiological roles on microtubules and its pathoconversion into NFTs.

Alzheimer's disease (AD) is the fastest-growing neurodegenerative disorder globally, with patient numbers expected to rise to 130 million by 2050. Insomnia, a prevalent comorbidity, exhibits a bidirectional relationship with AD: insomnia accelerates AD pathology, while AD worsens sleep disorders. This relationship has emerged as a key area of research. Current mechanisms involve oxidative stress, inflammatory responses, and glymphatic system dysfunction, yet a comprehensive review of these processes remains absent.

To conduct a visual analysis of the relationship between Alzheimer's disease and insomnia using CiteSpace.

Literature on "insomnia" and "Alzheimer's disease" published between January 1, 2000, and October 31, 2024, was retrieved from the Web of Science Core Collection. CiteSpace and VOSviewer software were used to analyze institutions, authors, and keywords.

A total of 1,907 articles were analyzed, revealing a consistent upward trend in publication volume. The United States and the Mayo Clinic were identified as leading contributors, producing 704 and 57 publications, respectively. Boeve Bradley F the most prolific author contributed 30 publications. Collaboration was actively observed among countries, institutions, and authors. High-frequency keywords identified were "Parkinson's disease," "cognitive impairment," and "sleep behavior disorder." Emerging research areas are likely to focus on "sleep quality" and the "glymphatic system."

This study is the first to apply bibliometric analysis to identify three key trends in AD and insomnia research: the dominance of the United States and Mayo Clinic, strong international collaboration, and a focus on critical areas such as cognitive impairment, the glymphatic system, and sleep interventions. Insomnia may accelerate AD progression via multiple pathways, indicating that enhancing sleep quality could provide new strategies for early intervention. Future research should prioritize advancing the clinical translation of sleep interventions and investigating the mechanisms of the glymphatic system.

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation, neurofibrillary tangles, neuroinflammation, and progressive cognitive decline, posing a significant global health challenge. Growing evidence suggests that dietary polyphenols may reduce the risk and progression of AD through multifaceted neuroprotective mechanisms. Polyphenols regulate amyloid proteostasis by inhibiting β/γ-secretase activity, preventing Aβ aggregation, and enhancing clearance pathways. Their strong antioxidant properties neutralize reactive oxygen species, chelate redox-active metals, and activate cytoprotective enzymes via Nrf2 signaling. This review examines the potential therapeutic targets, signaling pathways, and molecular mechanisms by which dietary polyphenols exert neuroprotective effects in AD, focusing on their roles in modulating amyloid proteostasis, oxidative stress, neuroinflammation, and cerebrovascular health. Polyphenols mitigate neuroinflammation by suppressing NF-κB signaling and upregulating brain-derived neurotrophic factor, supporting neuroplasticity and neurogenesis. They also enhance cerebrovascular health by improving cerebral blood flow, maintaining blood-brain barrier integrity, and modulating angiogenesis. This review examines the molecular and cellular pathways through which polyphenols exert neuroprotective effects, focusing on their antioxidant, anti-inflammatory, and amyloid-modulating roles. We also discuss their influence on key AD pathologies, including Aβ deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Insights from clinical and preclinical studies highlight the potential of polyphenols in preventing or slowing AD progression. Future research should explore personalized dietary strategies that integrate genetic and lifestyle factors to optimize the neuroprotective effects of polyphenols.

In this study, the role of phosphorylation in the liquid-liquid phase separation (LLPS) of tau, the underlying driving forces, and the potential implications of this separation on protein conformation and subsequent protein aggregation were investigated. We compared in vivo-produced phosphorylated tau (p-tau) and nonphosphorylated tau under different coacervation conditions without adding crowding agents. Our findings revealed that spontaneous phase separation occurs exclusively in p-tau, triggered by a temperature shift from 4 °C to room temperature, and is driven by electrostatic and hydrophobic interactions. The p-tau self-acervation is reversible with temperature changes. Native mass spectrometry detects only two to nine phosphate groups per p-tau molecule, highlighting the impact of phosphorylation on tau's structural flexibility. Cross-linking mass spectrometry showed fewer long-range contacts in p-tau, suggesting a looser conformation induced by phosphorylation. Phosphorylation-induced LLPS and RNA-induced LLPS occurred at different timeframes. However, neither tau nor p-tau formed fibrils without the addition of dextran sulfate or RNA as inducers. Using human kidney epithelial cells expressing the tau R domain fused with fluorescent proteins as reporter cells, we observed aggregates in the nuclear envelope (NE) only in the cells treated with LLPS-state p-tau, which correlates with NE occurrences reported in Alzheimer's disease brain sections. These findings provide deeper insights into the impact of phosphorylation on tau aggregation through an intermediate condensation phase, offering novel perspectives on neurodegenerative disease mechanisms.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, memory loss, and behavioural changes. While genetic predispositions and pathological processes have been the traditional focus, this review highlights the fundamental role of environmental factors, particularly nutrition, within the exposome framework in modulating the risk and progression of AD. The exposome, which includes the totality of environmental exposures in an individual's lifetime, provides a comprehensive approach to understanding the complex aetiology of AD. In this review, we explore the impact of dietary factors and cyclic nucleotide pathways (cAMP/cGMP) on AD, emphasizing the potential of dietary interventions as therapeutic strategies. We investigate key aspects of how nutrition affects the accumulation of β-amyloid, the aggregation of tau proteins, and neuroinflammation. We also examine the impact of specific nutrients on cognitive performance and the risk of AD. Additionally, we discuss the potential of nutraceuticals with anti-phosphodiesterase activity and the role of various animal models of AD (such as 5xFAD, 3xTg-AD, Tg2576, and APP/PS1 mice) in demonstrating the effects of dietary interventions on disease onset and progression.

Tau proteins as neurofibrillary tangles are one of the molecular hallmarks of Alzheimer's disease (AD) and play a central role in tauopathies, a group of age-related neurodegenerative disorders. The filament cores from diverse tauopathies share a common region of tau consisting of the R3-R4 microtubule-binding repeats and part of the C-terminal domain, but present a structural polymorphism. Unlike the fibril structure, the PTM signature of tau found in neuronal inclusions, more particularly hyperphosphorylation, is variable between individuals with the same tauopathy, giving rise to diverse strains with different seeding properties that could modulate the aggressiveness of tau pathology. Here, we investigate the conformation, function and seeding activity of two tau fragments and their GSK3β-phosphorylated variants. The R2Ct and R3Ct fragments encompass the aggregation-prone region of tau starting at the R2 and R3 repeats, respectively, and the full C-terminal domain including the PHF-1 epitope (S396, S400, S404), which undergoes a triple phosphorylation upon GSK3β activity. We found that the R3Ct fragment shows both a greater loss of function and pathological activity in seeding of aggregation than the R2Ct fragment which imposes a cross-seeding barrier. PHF-1 hyperphosphorylation induces a local conformational change with a propensity to adopt a β-sheet conformation in the region spanning residues 392-402, and exacerbates the seeding ability of fragments to induce aggregation by overcoming a cross-seeding barrier between tau variants.

In this study, we further characterized a non-transgenic model of tauopathy by examining tau protein changes using ELISA and Western blot upon inoculation of human tau oligomers (TO) and human tau synthetic pre-formed fibrils (TF) into the medial entorhinal cortex of Wistar rats. Our analyses showed that inoculation with TO did not significantly alter the ratio of phosphorylated tau at AT8 epitopes (pSer202/pThr205) to total tau protein in the hippocampus and entorhinal cortex, but only resulted in a decrease of phosphorylation at AT100 epitopes (pThr212/pSer214). As we previously observed an increase in AT8 immunostaining in both regions, this suggests method-dependent conformational alterations. In contrast, eleven months after inoculation, TF caused significant AT8 and PHF-1 (pSer396/pSer404) epitope-specific changes in tau phosphorylation in the hippocampus, but not in the entorhinal cortex, reflecting a more advanced stage of Alzheimer's disease (AD)-like changes compared to TO. Importantly, amyloid plaques appeared as early as four months post-inoculation with TO, preceding significant phosphorylation changes of tau, thus indicating that amyloid probably facilitates early tau seeding and spreading. This was corroborated by the observed dynamic changes in Aβ1-42 levels in cerebrospinal fluid, with initial decreases followed by increases, similar to patterns seen in transgenic mouse models of AD and in AD patients. Altogether, these findings lead us to conclude that changes in tau protein induce amyloid changes and vice versa, which is actually what defines AD as a unique neurodegenerative disease.

In recent years, targeted protein degradation (TPD) strategies leveraging the autophagy-lysosomal pathway (ALP) have transcended the limitations of conventional drug molecules, emerging as a highly promising approach for selectively eliminating disease-related proteins via the cell's intrinsic degradation machinery. These TPD methods, such as autophagosome-tethering compounds (ATTEC), autophagy-targeting chimera (AUTAC), AUTOphagy-TArgeting chimera (AUTOTAC), and chaperone-mediated autophagy (CMA) targeting chimera, exhibit efficacy in degrading misfolded protein aggregates associated with neurodegenerative disorders. Moreover, the excessive accumulation of misfolded proteins or protein complexes in the placenta has been identified as a significant contributor to preeclampsia (PE). Given the lack of effective treatments for PE, the application of autophagy-mediated TPD technology presents a novel therapeutic avenue. This review draws parallels between misfolded protein aggregates in neurodegenerative diseases and placenta-derived PE, integrating a substantial number of full-text studies. By harnessing TPD technologies grounded in the ALP, these autophagic degraders offer a pioneering approach for targeted therapy in PE by dismantling potential targets. Presently, there is limited exploration of ALP technology for identifying target proteins in the placenta. Nonetheless, we have proposed several potential target proteins, laying the groundwork for future therapeutic endeavors.

Highly reactive metabolic intermediates and other small molecules frequently react with amino acid side chains, leading to non-enzymatic posttranslational modifications (nPTMs) of proteins. The abundance of these modifications increases under high metabolic activity or stress conditions and can dramatically impact protein structure and function. Although protein quality control mechanisms typically mitigate the effects of these impaired proteins, in long-lived and degradation-resistant proteins, nPTMs accumulate. In some cases, such as cataract development and diabetes, clear links between nPTMs, aging, and disease progression have been established. In neurodegenerative diseases such as Alzheimer's and Parkinson's disease, a key question is whether accumulation of nPTMs is a cause or consequence of protein aggregation. This review focuses on major nPTMs found on proteins with central roles in neurodegenerative diseases such as α-synuclein, β-amyloid, and tau. We summarize current knowledge on the formation of these modifications and discuss their potential impact on disease onset and progression. Additionally, we examine what is known to date about how nPTMs impair cellular detoxification, repair, and degradation systems. Finally, we critically discuss the available methodologies to systematically investigate nPTMs at the molecular level and outline suitable approaches to study their effects on protein aggregation. We aim to foster more research into the role of nPTMs in neurodegeneration by adapting methodologies that have proven successful in studying enzymatic posttranslational modifications. Specifically, we advocate for site-specific incorporation of these modifications into target proteins using advanced chemical and molecular biology techniques.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neurofibrillary tangles (NFTs), senile plaques from Aβ deposits, neuronal inflammation, oxidative stress, and impaired neuronal transmission involving acetylcholine and glutamate. Diabetes patients are at a higher risk of developing AD-like pathology due to shared pathological and molecular mechanisms, including insulin resistance, oxidative stress, formation of advanced glycation end products (AGEs), and overactive immune systems. Current treatments of AD typically address only one aspect of the disease, rather than treating it as a multifactorial process. Targeting cerebral glucose-insulin metabolism has emerged as a promising strategy for AD management. Numerous studies show positive correlations between anti-diabetic drugs and AD management. Among these, DPP IV inhibitors have demonstrated significant therapeutic benefits against AD in experimental settings. DPP IV inhibitors have been shown to significantly reduce Aβ oligomerization, phosphorylated tau (p-tau), oxidative stress, and inflammatory markers, presenting a potentially effective approach for targeting AD-like pathology. Although preclinical data are promising, clinical trials are needed to validate these findings and establish the safety and efficacy of DPP IV inhibitors as a therapeutic intervention for AD. This could represent a novel approach for addressing both the metabolic and neurodegenerative aspects of AD.

Type 2 diabetes increases the risk of Alzheimer's disease (AD) dementia. Insulin signaling dysfunction exacerbates tau protein phosphorylation, a hallmark of AD pathology. However, the comprehensive impact of diabetes on patterns of AD-related phosphoprotein in the human brain remains underexplored.

We performed tandem mass tag-based phosphoproteome profiling in post mortem human brain prefrontal cortex samples from 191 deceased older adults with and without diabetes and pathologic AD.

Among 7874 quantified phosphosites, microtubule-associated protein tau (MAPT) phosphorylated at T529 and T534 (isoform 8 T212 and T217) were more abundant in AD and showed differential associations with diabetes. Network analysis of co-abundance patterns uncovered synergistic interactions between AD and diabetes, with one module exhibiting higher MAPT phosphorylation (15 MAPT phosphosites) and another displaying lower MAP1B phosphorylation (22 MAP1B phosphosites).

This study offers phosphoproteomics insights into AD in diabetes, shedding light on mechanisms that can inform the development of therapeutics for dementia.

The risk of Alzheimer's disease (AD) dementia is increased among older adults living with diabetes. The patterns of AD-related phosphoprotein in the human brain in older adults are differential among older adults living with diabetes. Microtubule-associated protein tau phosphorylated at T529 and T534 (isoform 8 T212 and T217) showed differential associations with diabetes. Phosphosite co-abundance networks of synergistic interactions between AD and diabetes were identified.

Phosphorylation plays a crucial role in both normal and disease processes involving the microtubule-associated protein tau. Physiologically, phosphorylation regulates tau's subcellular localization within neurons and is involved in fetal development and animal hibernation. However, abnormal phosphorylation of tau is linked to the formation of neurofibrillary tangles (NFTs) in various human tauopathies. Interestingly, the patterns of tau phosphorylation are similar in both normal and abnormal processes, leaving unclear whether phosphorylated tau retains its functional role in normal processes. The relationship between tau phosphorylation and NFT assembly in tauopathies is also still debated. To address these questions, we investigated the effects of tau phosphorylation on microtubule binding, cooperative protein envelope formation, and NFT filament assembly relevant to tauopathies. Consistent with previous results, our findings show that tau phosphorylation decreases tau's overall affinity for microtubules, but we reveal that phosphorylation more dramatically impacts the cooperativity between tau molecules during tau envelope formation along microtubules. Additionally, we observed that the specific pattern of phosphorylation, rather than overall phosphorylation level, strongly impacts the assembly of tau filaments in vitro . Our results reveal new insights into how tau phosphorylation impacts tau's physiological roles on microtubules and its pathoconversion into NFTs.

Alzheimer's disease, a common and progressive neurodegenerative disorder, is associated with alterations in hippocampal volume, as revealed by neuroimaging research. However, the causal links between the volumes of the hippocampus and its subfield structures with Alzheimer's disease remain unknown. A genetic correlation analysis using linkage disequilibrium score regression was conducted to identify hippocampal volumetric traits linked to Alzheimer's disease. Following this, to examine the causal links between Alzheimer's disease and hippocampal volumetric traits, we applied a two-sample Mendelian randomization approach, utilizing a bidirectional framework. Seven hippocampal volumetric traits were found as genetically correlated with Alzheimer's disease in the genetic correlation analysis and were then included in the Mendelian randomization analyses. Inverse variance weighted Mendelian randomization analyses revealed that increased volumes in the left whole hippocampus, left hippocampal body, right presubiculum head and right cornu ammonis 1 head were causally related to higher risks of Alzheimer's disease. Conversely, a higher risk of Alzheimer's disease was causally associated with decreased volumes of the left hippocampal body and left whole hippocampus. These results were validated through other Mendelian randomization approaches and sensitivity analysis. Our findings uncover bidirectional causal relationships between Alzheimer's disease and hippocampal volumetric traits, suggesting not only the potential significance of these traits in predicting Alzheimer's disease but also the reciprocal influence of Alzheimer's disease on hippocampal volumes.

Currently, Alzheimer's disease (AD) is one of the most frequent forms of dementia. From a molecular perspective, the molecular characteristics that better define this disease consist of abnormal protein deposits between neuronal cells, namely senile plaques (SPs) and neurofibrillary tangles (NFTs), consisting of protein aggregates of amyloid-β and hyperphosphorylated tau protein, respectively. In addition to these protein aggregates, a third molecular hallmark of AD consists of depleted neurotransmitter acetylcholine levels. To date, the treatments developed for this disease are mostly focused on the use of AChE inhibitors, presenting only a symptomatic approach against the disease instead of a cure. Triazines are nitrogen-containing heterocyclic compounds that, throughout the years, have attracted a lot of curiosity from medicinal chemists for presenting numerous biological properties and being widely present in nature. In particular, this class of compounds has been associated with inhibiting several biological targets, emerging as a promising class for developing new pharmacological agents. However, there is still a scarcity of knowledge regarding the potential of this type of compound against any of the hallmarks of AD. For this reason, this paper intends to fulfill this absence by highlighting the potential of a subclass of triazines, 1,3,5-triazines (sym-triazines), as promising molecules for developing novel AD treatments. Thus, an in-depth analysis of 1,3,5-triazine derivatives is performed regarding its inhibitory activity against AChE (cholinergic hypothesis) and its capability to inhibit amyloid-β formation and aggregation (amyloid hypothesis). Through this analysis, it is possible to indicate some structural features optimal for each described activity, a compilation that we believe to be essential for the scientific community in this never-ending pursuit.

With the continuous increase of the elderly population, there is an urgency to understand and develop relevant treatments for Alzheimer's disease and related dementias (ADRD). In tandem with this, the prevalence of health inequities continues to rise as disadvantaged communities fail to be included in mainstream research. The neural exposome poses as a relevant mechanistic approach and tool for investigating ADRD onset, progression, and pathology as it accounts for several different factors: exogenous, endogenous, and behavioral. Consequently, through the neural exposome, health inequities can be addressed in ADRD research. In this paper, we address how the neural exposome relates to ADRD by contributing to the discourse through defining how the neural exposome can be developed as a tool in accordance with machine learning. Through this, machine learning can allow for developing a greater insight into the application of transferring and making sense of experimental mouse models exposed to health inequities and potentially relate it to humans. The overall goal moving beyond this paper is to define a multitude of potential factors that can increase the risk of ADRD onset and integrate them to create an interdisciplinary approach to the study of ADRD and subsequently translate the findings to clinical research.

Alcohol use has recently emerged as a modifiable risk factor for Alzheimer's disease (AD). However, the neurobiological mechanisms by which alcohol interacts with AD pathogenesis remain poorly understood. In this chapter, we review the epidemiological and preclinical support for the interaction between alcohol use and AD. We hypothesize that alcohol use increases the rate of accumulation of specific AD-relevant pathologies during the prodromal phase and exacerbates dementia onset and progression. We find that alcohol consumption rates are increasing in adolescence, middle age, and aging populations. In tandem, rates of AD are also on the rise, potentially as a result of this increased alcohol use throughout the lifespan. We then review the biological processes in common between alcohol use disorder and AD as a means to uncover potential mechanisms by which they interact; these include oxidative stress, neuroimmune function, metabolism, pathogenic tauopathy development and spread, and neuronal excitatory/inhibitory balance (EIB). Finally, we provide some forward-thinking suggestions we believe this field should consider. In particular, the inclusion of alcohol use assessments in longitudinal studies of AD and more preclinical studies on alcohol's impacts using better animal models of late-onset Alzheimer's disease (LOAD).

Alzheimer's disease (AD) poses a significant worldwide health challenge, requiring novel approaches for improved models and treatment development. This comprehensive review emphasises the systematic development and improvement of a biomimetic brain environment to address the shortcomings of existing AD models and enhance the efficiency of screening potential drug treatments. We identify drawbacks in traditional models and emphasise the necessity for more physiologically accurate systems through an in-depth analysis of current literature. This review aims to study the development of an advanced AD model that accurately replicates key AD pathophysiological aspects using cutting-edge biomaterials and microenvironment design. Incorporating biomolecular elements like Tau proteins and beta-amyloid (Aβ) plaques improve the accuracy of illustrating disease mechanisms. The expected results involve creating a solid foundation for high-throughput screening with enhanced scalability, translational significance, and the possibility of speeding up drug discovery. Thus, this review fills the gaps in AD modelling and shows potential for creating precise and efficient drug treatments for AD.

The apolipoprotein E ( APOE ) ε4 allele is the strongest genetic risk factor for Alzheimer's disease (AD). ApoE is glycosylated with an O-linked Core-1 sialylated glycan at several sites, yet the impact and function of this glycosylation on AD biomarkers remains unclear. We examined apoE glycosylation in a cohort of cerebrospinal fluid (CSF, n=181) and plasma (n= 178) samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) stratified into 4 groups: cognitively normal (CN), Mild Cognitive Impairment (MCI), progressors and non-progressors based on delayed word recall performance over 4 years. We observed decreasing glycosylation from apoE2 > apoE3 > apoE4 in CSF, and in plasma (apoE3 > apoE4). ApoE glycosylation was reduced in the MCI compared with CN groups, and in progressors compared to non-progressors. In CSF, higher apoE glycosylation associated cross-sectionally with lower total tau (t-tau), p-tau181, and with higher Aβ 1-42 . Similar associations of apoE glycosylation with higher Aβ 1-42 were observed in plasma. In CSF, greater apoE4 glycosylation was associated with lower t-tau and p-tau181. Over a 6-year period, higher baseline levels of CSF apoE glycosylation predicted lower rates of increase in CSF t-tau and p-tau181 and lower rates of decrease in CSF Aβ 1-42 . These results indicate strong associations of apoE glycosylation with biomarkers of AD pathology independent of apoE genotype, warranting a deeper understanding of the functional role of apoE glycosylation on AD tau pathology.

Autism spectrum disorder (ASD) is a highly prevalent multifactorial disorder characterized by social deficits and stereotypies. Despite extensive research efforts, the etiology of ASD remains poorly understood. However, studies using preclinical models have identified the mechanistic target of rapamycin kinase (mTOR) signaling pathway as a key player in ASD-related features. This review examines genetic and environmental models of ASD, focusing on their association with the mTOR pathway. We organize findings on alterations within this pathway, providing insights about the potential mechanisms involved in the onset and maintenance of ASD symptoms. Our analysis highlights the central role of mTOR hyperactivation in disrupting autophagic processes, neural organization, and neurotransmitter pathways, which collectively contribute to ASD phenotypes. The review also discusses the therapeutic potential of mTOR pathway inhibitors, such as rapamycin, in mitigating ASD characteristics. These insights underscore the importance of the mTOR pathway as a target for future research and therapeutic intervention in ASD. This review innovates by bringing the convergence of disrupted mTOR signaling in preclinical models and clinical data associated with ASD.

Considerable uncertainty remains regarding the associations of multiple factors with brain health. We aimed to conduct an exposome-wide association study on neurodegenerative disease and neuropsychiatry disorders using data of participants from the UK Biobank. Multivariable Cox regression models with the least absolute shrinkage and selection operator technique as well as principal component analyses were used to evaluate the exposures in relation to common disorders of central nervous system (CNS). Restricted cubic splines were conducted to explore potential nonlinear correlations. Then, weighted standardized scores were generated based on the coefficients to calculate the joint effects of risk factors. We also estimated the potential impact of eliminating the unfavorable profiles of risk domains on CNS disorders using population attributable fraction (PAF). Finally, sensitivity analyses were performed to reduce the risk of reverse causality. The current study discovered the significantly associated exposures fell into six primary exposome categories. The joint effects of identified risk factors demonstrated higher risks for common disorders of CNS (HR = 1.278 ~ 3.743, p < 2e-16). The PAF varied by exposome categories, with lifestyle and medical history contributing to majority of disease cases. In total, we estimated that up to 3.7 ~ 64.1% of disease cases could be prevented.This study yielded modifiable variables of different categories and assessed their joint effects on common disorders of CNS. Targeting the identified exposures might help formulate effective strategies for maintaining brain health.

Aging is a complex biological process characterized by the gradual decline of cellular functions, increased susceptibility to diseases, and impaired stress responses. Hypoxia, defined as reduced oxygen availability, is a critical factor that influences aging through molecular pathways involving hypoxia-inducible factors (HIFs), oxidative stress, inflammation, and epigenetic modifications. This review explores the interconnected roles of hypoxia in aging, highlighting how hypoxic conditions exacerbate cellular damage, promote senescence, and contribute to age-related pathologies, including cardiovascular diseases, neurodegenerative disorders, cancer, metabolic dysfunctions, and pulmonary conditions. By examining the molecular mechanisms linking hypoxia to aging, we identify key pathways that serve as potential therapeutic targets. Emerging interventions such as HIF modulators, antioxidants, senolytics, and lifestyle modifications hold promise in mitigating the adverse effects of hypoxia on aging tissues. However, challenges such as the heterogeneity of aging, lack of reliable biomarkers, and safety concerns regarding hypoxia-targeted therapies remain. This review emphasizes the need for personalized approaches and advanced technologies to develop effective antiaging interventions. By integrating current knowledge, this review provides a comprehensive framework that underscores the importance of targeting hypoxia-induced pathways to enhance healthy aging and reduce the burden of age-related diseases.

Protein aggregation serves as a critical pathological marker in a spectrum of neurodegenerative diseases (NDs), including the formation of amyloid β (Aβ) and Tau neurofibrillary tangles in Alzheimer's disease, as well as α-Synuclein (α-Syn) aggregates in Parkinson's disease, Parkinson's disease-related dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). A significant proportion of patients with amyotrophic lateral sclerosis (ALS) exhibit TDP-43 aggregates. Moreover, a confluence of brain protein pathologies, such as Aβ, Tau, α-Syn, and TDP-43, has been identified in individual NDs cases, highlighting the intricate interplay among these proteins that is garnering heightened scrutiny. Importantly, protein aggregation is modulated by an array of factors, with burgeoning evidence suggesting that it frequently results from perturbations in protein homeostasis, influenced by the cellular membrane milieu, metal ion concentrations, post-translational modifications, and genetic mutations. This review delves into the pathological underpinnings of protein aggregation across various NDs and elucidates the intercommunication among disparate proteins within the same disease context. Additionally, we examine the pathogenic mechanisms by which diverse factors impinge upon protein aggregation, offering fresh perspectives for the future therapeutic intervention of NDs.

Recent studies underscore the role of gut and oral microbiota in influencing neuroinflammation through the microbiota-gut-brain axis, including in Alzheimer's disease (AD). This review aims to provide a comprehensive synthesis of recent findings on the involvement of gut and oral microbiota in the neuroinflammatory processes associated with AD, emphasizing novel insights and therapeutic implications. This review reveals that dysbiosis in AD patients' gut and oral microbiota is linked to heightened peripheral and central inflammatory responses. Specific bacterial taxa, such as Bacteroides and Firmicutes in the gut, as well as Porphyromonas gingivalis in the oral cavity, are notably altered in AD, leading to significant changes in microglial activation and cytokine production. Gut microbiota alterations are associated with increased intestinal permeability, facilitating the translocation of endotoxins like lipopolysaccharides (LPS) into the bloodstream and exacerbating neuroinflammation by activating the brain's toll-like receptor 4 (TLR4) pathways. Furthermore, microbiota-derived metabolites, including short-chain fatty acids (SCFAs) and amyloid peptides, can cross the blood-brain barrier and modulate neuroinflammatory responses. While microbial amyloids may contribute to amyloid-beta aggregation in the brain, certain SCFAs like butyrate exhibit anti-inflammatory properties, suggesting a potential therapeutic avenue to mitigate neuroinflammation. This review not only highlights the critical role of microbiota in AD pathology but also offers a ray of hope by suggesting that modulating gut and oral microbiota could represent a novel therapeutic strategy for reducing neuroinflammation and slowing disease progression.

This review delves into the entorhinal cortex (EC) as a central player in the pathogenesis of Alzheimer's Disease (AD), emphasizing its role in the accumulation and propagation of tau pathology. It elucidates the multifaceted functions of the EC, encompassing memory formation, spatial navigation, and olfactory processing, while exploring how disruptions in these processes contribute to cognitive decline in AD. The review discusses the intricate interplay between tau pathology and EC vulnerability, highlighting how alterations in neuronal firing patterns and synaptic function within the EC exacerbate cognitive impairments. Furthermore, it elucidates how specific neuronal subtypes within the EC exhibit differential susceptibility to tau-induced damage, contributing to disease progression. Early detection methods, such as imaging techniques and assessments of EC blood flow, are examined as potential tools for identifying tau pathology in the preclinical stages of AD. These approaches offer promise for improving diagnostic accuracy and enabling timely intervention. Therapeutic strategies targeting tau pathology within the EC are explored, including the clearance of pathological tau aggregates and the inhibition of tau aggregation processes. By understanding the molecular and cellular mechanisms underlying EC vulnerability, researchers can develop more targeted and effective interventions to slow disease progression. The review underscores the importance of reliable biomarkers to assess disease progression and therapeutic efficacy in clinical trials targeting the EC. Ultimately, it aims to contribute to the development of more effective management strategies for AD, emphasizing the translation of research findings into clinical practice to address the growing societal burden of the disease.

Brain structural alterations begin long before the presentation of brain disorders; therefore, we aimed to systematically investigate a wide range of influencing factors on neuroimaging markers of brain health.

Utilizing data from 30,651 participants from the UK Biobank, we explored associations between 218 modifiable factors and neuroimaging markers of brain health. We conducted an exposome-wide association study using the least absolute shrinkage and selection operator (LASSO) technique. Restricted cubic splines (RCS) were further employed to estimate potential nonlinear correlations. Weighted standardized scores for neuroimaging markers were computed based on the estimates for individual factors. Finally, stratum-specific analyses were performed to examine differences in factors affecting brain health at different ages.

The identified factors related to neuroimaging markers of brain health fell into six domains, including systematic diseases, lifestyle factors, personality traits, social support, anthropometric indicators, and biochemical markers. The explained variance percentage of neuroimaging markers by weighted standardized scores ranged from 0.5% to 7%. Notably, associations between systematic diseases and neuroimaging markers were stronger in older individuals than in younger ones.

This study identified a series of factors related to neuroimaging markers of brain health. Targeting the identified factors might help in formulating effective strategies for maintaining brain health.

Oryza sativa is a globally recognized staple food, rich in essential phyto-phenolic compounds such as γ-Oryzanol (OZ), Ferulic acid (FA), and Ellagic acid (EA). These phytochemicals are known for their potential to beneficially modulate molecular biochemistry. The present investigation aimed to evaluate the neuroprotective and cognitive enhancement effects of Oryza sativa phyto-phenolics in a model of early-onset Alzheimer's disease (EOAD) induced by Aβ (1-42) in animals. In-silico studies suggested that FA, OZ, and EA have target specificity for Aβ, with EA being further selected based on its potent in-vitro Aβ anti-aggregatory effects for exploring neurodegenerative conditions. The in-vivo experiments demonstrated that EA exerts therapeutic effects in Aβ-induced EOAD, modulating both biochemical and behavioral outcomes. EA treatment at two dose levels, EA70 and EA140 (70 μM and 140 μM, respectively, administered i.c.v.), significantly counteracted Aβ aggregation and modulated the Ca2⁺/Calpain/GSK-3β/CDK5 signaling pathways, exhibiting anti-tauopathy effects. Additionally, EA was shown to exert anti-inflammatory effects by preventing astroglial activation, modulating FAIM-L expression, and protecting against TNF-α-induced apoptotic signals. Moreover, the neuromodulatory effects of EA were attributed to the regulation of CREB levels, Dnm-1 expression, and synaptophysin levels, thereby enhancing LTP and synaptic plasticity. EA also induced beneficial cytological and behavioral changes, improving both long-term and short-term spatial memory as well as associative learning behavior in the animal model, which underscores its cognitive enhancement properties.

Asiatic acid (AA) has previously shown its neuroprotective effects, but low oral bioavailability limits its penetration into the brain. This study aimed to investigate the effect of intranasal AA administration in mice with memory dysfunction induced by scopolamine. Mice received either intranasal AA (INAA), oral AA (POAA3 or POAA30), or donepezil, followed by scopolamine for 10 days. Morris water maze (MWM) was performed on days 0-5, 30 min after treatment. Locomotor activity was conducted on day 6 followed by brain collection. In MWM, INAA treatment had significantly reduced escape latency on days 2-4, while POAA3 decreased escape latency on day 3 and POAA30 and donepezil decreased escape latency on day 4. INAA inhibited acetylcholinesterase activity, increased catalase protein expression, and decreased malondialdehyde levels in the brain tissue. Therefore, intranasal administration of AA produced a rapid onset in the protection of learning and memory deficits induced by scopolamine through acetylcholinesterase inhibition and antioxidant effect.

Alzheimer's disease (AD) still prevails and continues to increase indiscriminately throughout the 21st century, and is thus responsible for the depreciating quality of health and associated sectors. AD is a progressive neurodegenerative disorder marked by a significant amassment of beta-amyloid plaques and neurofibrillary tangles near the hippocampus, leading to the consequent loss of cognitive abilities. Conventionally, amyloid and tau hypotheses have been established as the most prominent in providing detailed insight into the disease pathogenesis and revealing the associative biomarkers intricately involved in AD progression. Nanotheranostic deliberates rational thought toward designing efficacious nanosystems and strategic endeavors for AD diagnosis and therapeutic implications. The exceeding advancements in this field enable the scientific community to envisage and conceptualize pharmacokinetic monitoring of the drug, sustained and targeted drug delivery responses, fabrication of anti-amyloid therapeutics, and enhanced accumulation of the targeted drug across the blood-brain barrier (BBB), thus giving an optimistic approach towards personalized and precision medicine. Current methods idealized on the design and bioengineering of an array of nanoparticulate systems offer higher affinity towards neurocapillary endothelial cells and the BBB. They have recently attracted intriguing attention to the early diagnostic and therapeutic measures taken to manage the progression of the disease. In this article, we tend to furnish a comprehensive outlook, the detailed mechanism of conventional AD pathogenesis, and new findings. We also summarize the shortcomings in diagnostic, prognostic, and therapeutic approaches undertaken to alleviate AD, thus providing a unique window towards nanotheranostic advancements without disregarding potential drawbacks, side effects, and safety concerns.

Alzheimer's disease (AD) is the most widespread and irreversible form of dementia and accounts for more than half of dementia cases. The most significant risk factors for AD are aging-related exacerbations, degradation of anatomical pathways, environmental variables and mitochondrial dysfunction. Finding a decisive therapeutic solution is a major current issue. Nuanced interactions between major neuropathological mechanisms in AD in patients and microbiome have recently gained rising attention. The presence of bacterial amyloid in the gut triggers the immune system, resulting in increased immune feedbacks and endogenous neuronal amyloid within the CNS. Also, early clinical research revealed that changing the microbiome with beneficial bacteria or probiotics could affect brain function in AD. New approaches focus on the possible neuroprotective action of disease-modifying medications in AD. In the present review, we discuss the impact of the gut microbiota on the brain and review emerging research that suggests a disruption in the microbiota-brain axis can affect AD by mediating neuroinflammation. Such novel methods could help the development of novel therapeutics for AD.