Intracellular accumulation of aberrantly phosphorylated aggregated tau protein can contribute to neuronal dysfunction associated with many neurodegenerative diseases. Thus, removing such tau species is an attractive therapeutic hypothesis for these diseases. Targeted protein degradation (TPD) strategies leveraging the autophagy-lysosome pathway (ALP) are promising approaches to decrease protein aggregates by designating them for degradation. Here, we developed a novel heterobifunctional molecule, MRL828, combining a tau pathology-binding ligand and modified guanine moiety based on the autophagy-targeting chimaera technology to selectively designate aggregated tau proteins for clearance via the ALP. Surprisingly, the MRL828-dependent decrease in intracellular tau aggregates was dependent on the autophagosome, but not the lysosome. MRL828 treatment led to autophagosome-dependent secretion of oligomeric and phosphorylated tau species, suggesting a reduction of intracellular tau aggregates via secretory autophagy rather than degradation via the ALP. This work highlights a novel mechanism of action (MOA) of an ALP-based heterobifunctional molecule and a potential new strategy for the cellular removal of proteins of interest.

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.

Autophagy is a pro-survival process that regulates the degradation and renewal of cellular components, making it a crucial mechanism for cellular homeostasis. There are selective forms of autophagy that are specific to a number of substrates, such as pathogens (bacteria or viruses), protein aggregates or excess/damaged organelles. These processes involve as key players autophagy receptors, that link the cargo to be degraded to the autophagic machinery. Among them, NDP52 (also known as CALCOCO2) has been described to act as a "bridge" between the autophagy machinery and (1) damaged mitochondria in the mitophagy process; (2) pathogens during xenophagy or (3) proteins in the process of aggrephagy. The aim of this review is to summarize the major functions of NDP52, and to highlight the existence of two human NDP52 variants that have been described as risk or protective factors for Crohn's disease or Multiple Sclerosis and Alzheimer's disease patients, respectively. As these three diseases share common pathological features that lead to inflammation, such as mitochondria or gut microbiota dysfunctions, but also pathogenic infections, it seems clear that NDP52 could be a key player at the crossroad by acting indirectly on inflammation, and therefore a potential target for clinical applications and benefits.

Alzheimer's Disease (AD) is a neurodegenerative condition characterised by cognitive decline and memory impairment. Recent research highlights the important role of hypoxia, a state of insufficient oxygen availability, in exacerbating AD pathogenesis.

Through the use of a number of different search engines like Scopus, PubMed, Bentham, and Elsevier databases, a literature review was carried out for investigating the role of hypoxia mediated pathobiology in AD. Only peerreviewed articles published in reputable journals in English language were included. Conversely, non-peer-reviewed articles, conference abstracts, and editorials were excluded, along with studies lacking experimental or clinical relevance or those unavailable in full text.

Hypoxia exacerbates core pathological features such as oxidative stress, neuroinflammation, mitochondrial dysfunction, amyloid-beta (Aβ) dysregulation, and hyperphosphorylation of tau protein. These interlinked mechanisms establish a self-perpetuating cycle of neuronal damage, accelerating disease progression. Addressing hypoxia as a modifiable risk factor offers potential for both prevention and treatment of AD. Exploring hypoxia and the HIF signalling pathway may help counteract the neuropathological and symptomatic effects of neurodegeneration.

Neurodegenerative tauopathies are characterized by the pathological hyperphosphorylation of tau proteins that subsequently form aggregates. Tau PET tracers with affinity to bind these pathological tau aggregates have been developed to measure disease progression and to support therapeutic drug development. In this review, we summarize the pathophysiology of tau throughout the range of neurodegenerative tauopathies. We outline the available first- and second-generation tau PET tracers, with a focus on new tau PET tracer developments, and discuss the quantification of tau PET images. Next, we summarize how tau PET relates to cerebrospinal fluid and plasma tau biomarkers. Finally, we review the current recommendations on the clinical use of tau PET versus fluid tau biomarkers in diagnosis, prognosis and treatment development.

Growing evidence links tau-related neurodegeneration with insulin resistance and type 2 diabetes (T2D), though the underlying mechanisms remain unclear. Our previous research identified HMGA1 as crucial for insulin receptor (INSR) expression, with defects in the HMGA1 gene associated with insulin resistance and T2D. Here, we explore HMGA1 deficiency as a potential contributor to tauopathies, such as Alzheimer's disease (AD), and its connection to insulin resistance.

Immunoblot analyses, protein-DNA interaction studies, ChIP-qPCR, and reporter gene assays were conducted in human and mouse neuronal cell models. Tau immunohistochemistry, behavioural studies, and brain glucose metabolism were analysed in Hmga1-knockout mice. Additionally, a case-control study investigated the relationship between HMGA1 and tau pathology in patients with tauopathy, carrying or not the HMGA1 rs146052672 variant, known to reduce HMGA1 protein levels and increase the risk of insulin resistance and T2D.

We show that HMGA1 regulates tau protein expression primarily through the specific repression of MAPT gene transcription. In both human neuronal cells and primary mouse neurons, tau mRNA and protein levels were inversely correlated with HMGA1 expression. This inverse relationship was further confirmed in the brain of Hmga1-knockout mice, where tau was overexpressed, INSR was downregulated, and brain glucose uptake was impaired. Additionally, the rs146052672 variant was more common in patients with tauopathy (12/69, 17.4%) than in controls (10/200, 5.0%) (p = 0.001), and carriers of this variant exhibited more severe disease progression and poorer therapeutic outcomes.

These findings suggest that HMGA1 deficiency may drive tau pathology, linking tauopathies to insulin resistance and providing new insights into the relationship between metabolic and neurodegenerative disorders. Furthermore, our observation that over 17% of individuals with tauopathy exhibit a deficit in HMGA1 protein production could have significant clinical implications, potentially guiding the development of therapeutic strategies targeting this specific defect.

See acknowledgements section.

Abnormal accumulation of tau proteins in the brain is a hallmark of neurodegenerative diseases such as Alzheimer's disease and is closely linked with neuronal cell death. Tau accumulation is a prominent therapeutic target for Alzheimer's disease, since tau accumulation correlates well with the disease progression, and tau-targeting drugs hold potentials to halt the disease progression. Given the differential response of human and mouse neuronal cells, there is a critical need for a human cellular platform to quickly screen for tau-related neurodegenerative disease therapeutics. However, inducing rapid, tau-dependent neuronal cell death in human models remains challenging. In this study, we established a human cellular model capable of inducing tau aggregation-dependent neuronal cell death within two weeks via tau overexpression. Additionally, we demonstrated the neuroprotective efficacy of known tau-targeting compounds within this system. These findings suggest that our cellular model recapitulates the molecular pathogenesis of tau-induced neurodegeneration and could serve as a valuable platform for drug screening in tauopathies.

Tau protein accumulation is linked to dementia progression in Alzheimer's disease (AD), with potential co-pathologies contributing to it. The progression of dementia in patients with AD varies between individuals, and the association between co-pathology and heterogeneity in dementia progression rate remains unclear. We used longitudinal cohort data, postmortem brain tissues, and biochemical methods such as immunoassays and proteomic profiling to investigate the molecular components associated with progression rate. We report that AD with comorbidities, such as dementia with Lewy bodies (DLB) and TDP-43 pathology, progress faster than AD alone. Patients with AD-DLB had higher levels of soluble oligomeric tau proteins and lower levels of insoluble tau proteins compared to those with AD alone. Our data suggest that α-synuclein fibrils may enhance tau aggregation through cross-seeding. The prefrontal cortex is more vulnerable to Lewy body pathology than the temporal cortex, and Tau and α-synuclein aggregate in distinct neuronal populations, indicating selective neuronal and regional vulnerability to their respective pathologies. Dysfunctional metabolic pathways were more strongly associated with patients having fast-progressing AD-DLB. Our study suggests that comorbidities, such as α-synuclein aggregation and metabolic dysfunctions, are associated with rapidly progressing AD patients, highlighting the importance of patient subgrouping for clinical trials.

In tauopathies, defects in autophagy-lysosomal protein degradation are thought to contribute to the abnormal accumulation of aggregated tau. Recent studies have shown that (-)-Epicatechin (Epi), a dietary flavonoid belonging to the flavan-3-ol subgroup, improves blood flow, modulates metabolic profiles, and prevents oxidative damage. However, less research has explored the effects of Epi on tauopathies. Here, we found that Epi rescued cognitive deficits in P301S tau transgenic mice, a model exhibiting characteristics of tauopathies like frontotemporal dementia and Alzheimer's disease, and attenuated tau pathology through autophagy activation. Proteomic and biochemical analyses revealed that P301S mice exhibit deficits in autophagosome formation via modulating mTOR, consequently inhibiting autophagy. Epi inhibited the mTOR signaling pathway to promote autophagosome formation, which is essential for the clearance of tau aggregation. By using chloroquine (CQ) to inhibit autophagy in vivo, we further confirmed that Epi induced tau degradation via the autophagy pathway. Lastly, Epi administration was also found to improve cognition by reversing spine decrease and neuron loss, as well as attenuating neuroinflammation. Our findings suggest that Epi promoted tau clearance by activating autophagy, indicating its potential as a promising therapeutic candidate for tauopathies.

Chronic traumatic encephalopathy (CTE) is a unique tauopathy mostly diagnosed in contact sports athletes, such as those active in American football, boxing, soccer, etc. The hyperphosphorylated fibrillar aggregates composed of self-assembled tau protein are the pathological hallmark of CTE, and inhibiting the aggregation or disassociating the fibrillar aggregates has been considered a promising avenue to prevent or treat CTE. Caffeine (CA) is a well-known psychostimulant and can be found in coffee, tea, and soft drinks. In vitro experiments revealed that CA could effectively inhibit wild-type tau aggregation and disassemble preformed fibrils. However, the atomic effect and the underlying molecular mechanisms remain largely elusive. In this study, we performed a multitude of replica exchange with solute tempering 2 (REST2) and conventional molecular dynamics (CMD) simulations of 43.8 μs in total on tau models with and without CA, including the third and fourth microtubule-binding repeats (R3-R4) tau monomer and CTE-related R3-R4 tau protofibril and fibril. The results revealed that CA could prominently inhibit the β-sheet formation of the monomer and disrupt the β-sheet structure of the protofibril, inducing the monomer and protofibril to adopt loosely packed or extended conformations. H-bonding and π-π stacking interactions drove the binding of CA on the monomer, while hydrophobic interactions made an extra contribution to the binding of CA on the protofibril. Strikingly, CA could stably bind to the hydrophobic cavity of the protofibril, which might occupy the space and prevent the entering of the aggregation cofactor. What is more, CA destabilized the fibril and played a role in reversing the liquid-to-solid phase transition (LSPT) of tau. Our study systematically uncovered the atomic-level effect of CA on tau aggregation, which offers a theoretical foundation for the design of drugs to prevent or treat CTE.

Proteomic profiling of Alzheimer's disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with Aβ since the early disease stage, but their roles in disease progression are not fully understood. Here we present that MDK attenuates Aβ assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model. MDK protein mitigates fibril formation of both Aβ40 and Aβ42 peptides in Thioflavin T fluorescence assay, circular dichroism, negative stain electron microscopy, and NMR analysis. Knockout of Mdk gene in 5xFAD increases amyloid formation and microglial activation. Further comprehensive mass spectrometry-based profiling of whole proteome and detergent-insoluble proteome in these mouse models indicates significant accumulation of Aβ and Aβ-correlated proteins, along with microglial components. Thus, our structural and mouse model studies reveal a protective role of MDK in counteracting amyloid pathology in Alzheimer's disease.

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.

The gallotannin 1,2,3,4,6-Penta-O-Galloyl-β-D-Glucose (β-PGG) has recently garnered scientific interest due to its potent antioxidant, anti-inflammatory and neuroprotective properties. Alzheimer's disease (AD), a neurodegenerative disorder marked by neuroinflammation, oxidative stress, cholinergic dysfunction, accumulation of amyloid β (Aβ), tau and metal ions, may benefit from β-PGG interventions. This review synthesises existing literature to explore the therapeutic potential of β-PGG in AD. Experimental evidence suggests that β-PGG can suppress pro-inflammatory mediator release and inhibit NF-κB and MAPK signalling pathways, both critical in AD progression. In vitro studies highlight β-PGG's ability to scavenge free radicals, enhance antioxidant enzyme function, and prevent lipid peroxidation, well-known phenomena in AD. Additionally, neuroprotection may be conferred by β-PGG's capacity to reduce metal ion accumulation, inhibit Aβ and tau aggregation, and modulate cholinergic neurotransmission in vitro. In summary, while β-PGG shows promise in targeting AD hallmarks in vitro, further in vivo studies are crucial to validate its therapeutic potential.

Alzheimer's disease (AD) remains a significant healthcare challenge, necessitating innovative therapeutic approaches to address its complex and multifactorial nature. Traditional drug discovery strategies targeting single molecular targets are not sufficient for the effective treatment of AD. In recent years, MTDLs have emerged as promising candidates for AD therapy, aiming to simultaneously modulate multiple pathological targets. Among the various strategies employed in MTDL design, pharmacophore hybridization offers a versatile approach to integrate diverse pharmacophoric features within a single molecular scaffold. This strategy provides access to a wide array of chemical space for the design and development of novel therapeutic agents. This review, therefore, provides a comprehensive overview of skeletal diversity exhibited by MTDLs designed recently for AD therapy based on pharmacophore hybridization approach. A diverse range of pharmacophoric elements and core scaffolds hybridized to construct MTDLs that has the potential to target multiple pathological features of AD including amyloid-beta aggregation, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress, and neuroinflammation are discussed. Through the comprehensive analysis and integration of structural insights of key biomolecular targets, this review aims to enhance optimization efforts in MTDL design, ultimately striving towards a comprehensive cure for the multifaceted pathophysiology of the disease.

Diabetic retinal neurodegeneration (DRN) is an early manifestation of diabetic retinopathy (DR) characterized by neurodegeneration that precedes microvascular abnormalities in the retina. DRN is characterized by apoptosis of retinal ganglion cells (involves alterations in retinal ganglion cells [RGCs], photoreceptors, amacrine cells and bipolar cells and so on), reactive gliosis, and reduced retinal neuronal function. Tau, a microtubule-associated protein, is a key mediator of neurotoxicity in neurodegenerative diseases, with functions in phosphorylation-dependent microtubule assembly and stabilization, axonal transport, and neurite outgrowth. The hyperphosphorylated tau (p-tau) loses its ability to bind to microtubules and aggregates to form paired helical filaments (PHFs), which further form neurofibrillary tangles (NFTs), leading to abnormal cell scaffolding and cell death. Studies have shown that p-tau can cause degeneration of RGCs in DR, making tau pathology a new pathophysiological model for DR. Here, we review the mechanisms by which p-tau contribute to DRN, including insulin resistance or lack of insulin, mitochondrial damage such as mitophagy impairment, mitochondrial axonal transport defects, mitochondrial bioenergetics dysfunction, and impaired mitochondrial dynamics, Abeta toxicity, and inflammation. Therefore, this article proposes that tau protein hyperphosphorylation plays a crucial role in the pathogenesis of DRN and may serve as a novel therapeutic target for combating DRN.

Biomolecular condensates (BMCs) are membrane-less protein compartments with physiological and pathological relevance. The formation of BMCs is driven by a process known as liquid-liquid phase separation (LLPS), a field that has largely focused on the study of micron-sized condensates. However, there have been recent studies showing that proteins that undergo LLPS also form nanometer-sized condensates. These nanometer-sized condensates, or nanocondensates, are distinct from microcondensates and potentially exhibit more relevance in cell biology. The field of nanocondensate research is in its infancy, with limited biophysical studies of these structures. Here, we studied condensate formation and dissolution of wild-type and disease-linked (hyperphosphorylated and missense mutated) Tau. We investigated the effects of solution condition modulation on nanocondensate formation and dissolution, and observed that Tau condensation is strongly regulated by electrostatic forces and less affected by hydrophobic disruption. We observed that all three Tau variants studied shared condensate formation properties when in solution conditions with the same ionic strength. However, hyperphosphorylated and missense-mutated Tau exhibited higher resistance to dissolution compared to wild-type Tau. This study uncovers additional distinctions between different types of condensates, which provides further insight into the distinctions between physiological and pathological condensates.

Protein responses to environmental stress, particularly temperature fluctuations, have long been a subject of investigation, with a focus on how proteins maintain homeostasis and exhibit thermoresponsive properties. While UCST-type (upper critical solution temperature) phase behavior has been studied extensively and can now be predicted reliably using computational models, LCST-type (lower critical solution temperature) phase transitions remain less explored, with a lack of computational models capable of accurate prediction. This gap limits our ability to probe fully how proteins undergo phase transitions in response to temperature changes. Here, we introduce Mpipi-T, a residue-level coarse-grained model designed to predict LCST-type phase behavior of proteins. Parametrized using both atomistic simulations and experimental data, Mpipi-T accounts for entropically driven protein phase separation that occurs upon heating. Accordingly, Mpipi-T predicts temperature-driven protein behavior quantitatively in both single- and multi-chain systems. Beyond its predictive capabilities, we demonstrate that Mpipi-T provides a framework for uncovering the molecular mechanisms underlying heat stress responses, offering new insights into how proteins sense and adapt to thermal changes in biological systems.

Tau plays an important role in modulating axonal microtubules in neurons, while intracellular tau aggregates are found in many neurodegenerative disorders. Tubulin binding sites are found in tau's proline-rich region (PRR), microtubule binding repeats (MTBRs), and pseudo-repeat (R'). Tau phosphorylation sites, which cluster with high frequency within the PRR, regulate tubulin interactions and correlates with disease. Here, we use fluorescence correlation spectroscopy and structural mass spectrometry techniques to characterize the impact of phosphomimic mutations in the PRR on tau function. We find that phosphomimics cumulatively diminish tubulin dimer binding and slow microtubule polymerization. Additionally, we map two ∼15 residue regions of the PRR as primary tubulin dimer binding sites and propose a model in which PRR enhances lateral interactions between tubulin dimers, complementing the longitudinal interactions observed for MTBR. Our study provides insight into the previously overlooked relevance of tau's PRR in functional interactions with tubulin dimers.

Cerebral amyloid angiopathy (CAA) is driven by vascular Aβ (amyloid-beta) deposition, which can be detected as reduced Aβ species in cerebrospinal fluid (CSF). We sought to identify relationships between CSF Aβ and tau concentrations and various manifestations of CAA.

This is a retrospective cross-sectional single-center study of patients diagnosed with CAA per Boston Criteria version 2.0, had magnetic resonance imaging brain scans, and underwent CSF testing for Aβ and tau concentrations between 2008 and 2022. Associations between clinical/magnetic resonance imaging features and CSF biomarker concentrations were investigated with univariate and multivariate models.

We identified 31 patients aged 69.6±8.4 years, of whom 20 presented with cognitive complaints, 9 with CAA-related macrohemorrhage (lobar intraparenchymal or convexity subarachnoid hemorrhage), and 2 with transient focal neurological episodes. Presence of macrohemorrhage (301.8±112 pg/mL versus 400.9±123 pg/mL, P=0.029), cortical superficial siderosis (309.6±131 mg/dL versus 412.3±100 pg/mL, P=0.021), and severe enlarged perivascular spaces in centrum semiovale (285.8±91 pg/mL versus 428.3±117 pg/mL, P<0.001) were associated with lower Aβ42 concentrations. Aβ42 concentrations inversely correlated with the number of these manifestations, being lowest in patients having all three. Patients with cognitive complaints had higher t-tau (total tau; 551±320 pg/mL versus 317.2±141 pg/mL, P=0.03) and trended toward having higher p-tau (phosphorylated tau at threonine 181) concentrations (75.69±39 pg/mL versus 49.24±22 pg/mL, P=0.05).

Lower CSF Aβ42, suggesting higher amyloid burden, is associated with CAA-related macrohemorrhages and severe enlarged perivascular spaces in centrum semiovale, suggesting potential mechanistic links and CSF Aβ42 as a potential biomarker for progression of CAA. CSF tau concentrations are linked to cognitive complaints, likely representing comorbid Alzheimer disease pathology.

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Amyloid-β (Aβ) accumulation and neurofibrillary tangles are two key histological features resulting in progressive and irreversible neuronal loss and cognitive decline. The macrophages of the central nervous system (CNS) belong to the innate immune system and comprise parenchymal microglia and CNS-associated macrophages (CAMs) at the CNS interfaces (leptomeninges, perivascular space and choroid plexus). Microglia and CAMs have received attention as they may play a key role in disease onset and progression e. g., by clearing amyloid beta (Aβ) through phagocytosis. Genome-wide association studies (GWAS) have revealed that human microglia and CAMs express numerous risk genes for AD, further highlighting their potentially critical role in AD pathogenesis. Microglia and CAMs are tightly controlled by environmental factors, such as the host microbiota. Notably, it was further reported that the composition of the gut microbiota differed between AD patients and healthy individuals. Hence, emerging studies have analyzed the impact of gut bacteria in different preclinical mouse models for AD as well as in clinical studies, potentially enabling promising new therapeutic options.

There are limited data regarding cerebrospinal fluid (CSF) and plasma biomarkers among patients with Cerebral Amyloid Angiopathy (CAA). We sought to investigate the levels of four biomarkers [β-amyloids (Aβ42 and Aβ40), total tau (tau) and phosphorylated tau (p-tau)] in CAA patients compared to healthy controls (HC) and patients with Alzheimer Disease (AD).

A systematic review and meta-analysis of published studies, including also a 5 year single-center cohort study, with available data on CSF and plasma biomarkers in symptomatic sporadic CAA versus HC and AD was conducted. Biomarkers' comparisons were investigated using random-effects models based on the ratio of mean (RoM) biomarker concentrations. RoM < 1 and RoM > 1 indicate lower and higher biomarker concentration in CAA compared to another population, respectively.

We identified nine cohorts, comprising 327 CAA patients (mean age: 71 ± 5 years; women: 45%) versus 336 HC (mean age: 65 ± 5 years; women: 45%) and 384 AD patients (mean age: 68 ± 3 years; women: 53%) with available data on CSF biomarkers. CSF Aβ42 levels [RoM: 0.47; 95% CI: 0.36-0.62; p < 0.0001], Aβ40 levels [RoM: 0.70; 95% CI: 0.63-0.79; p < 0.0001] and the ratio Aβ42/Aβ40 [RoM: 0.62; 95% CI: 0.39-0.98; p = 0.0438] differentiated CAA from HC. CSF Aβ40 levels [RoM: 0.73; 95% CI: 0.64-0.83; p = 0.0003] differentiated CAA from AD. CSF tau and p-tau levels differentiated CAA from HC [RoM: 1.71; 95% CI: 1.41-2.09; p = 0.0002 and RoM: 1.44; 95% CI: 1.20-1.73; p = 0.0014, respectively] and from AD [RoM: 0.65; 95% CI: 0.58-0.72; p < 0.0001 and RoM: 0.64; 95% CI: 0.57-0.71; p < 0.0001, respectively]. Plasma Aβ42 [RoM: 1.14; 95% CI: 0.89-1.45; p = 0.2079] and Aβ40 [RoM: 1.07; 95% CI: 0.91-1.25; p = 0.3306] levels were comparable between CAA and HC.

CAA is characterized by a distinct CSF biomarker pattern compared to HC and AD. CSF Aβ40 levels are lower in CAA compared to HC and AD, while tau and p-tau levels are higher in CAA compared to HC, but lower in comparison to AD patients.

Dystrophic neurites (also termed axonal spheroids) are found around amyloid deposits in Alzheimer's disease (AD), where they impair axonal electrical conduction, disrupt neural circuits and correlate with AD severity. Despite their importance, the mechanisms underlying spheroid formation remain incompletely understood. To address this, we developed a proximity labeling approach to uncover the proteome of spheroids in human postmortem and mouse brains. Additionally, we established a human induced pluripotent stem cell (iPSC)-derived AD model enabling mechanistic investigation and optical electrophysiology. These complementary approaches revealed the subcellular molecular architecture of spheroids and identified abnormalities in key biological processes, including protein turnover, cytoskeleton dynamics and lipid transport. Notably, the PI3K/AKT/mTOR pathway, which regulates these processes, was activated in spheroids. Furthermore, phosphorylated mTOR levels in spheroids correlated with AD severity in humans. Notably, mTOR inhibition in iPSC-derived neurons and mice ameliorated spheroid pathology. Altogether, our study provides a multidisciplinary toolkit for investigating mechanisms and therapeutic targets for axonal pathology in neurodegeneration.

Dopamine (DA) is one of the most important neurotransmitters. Its oxidation leads to electrophilic quinone, which covalently modifies nucleophilic residues in proteins, resulting in 'dopamination'. Individual dopaminated proteins have been studied, most of which were functionally damaged by dopamination. Here, we developed a quantitative chemoproteomic strategy to site-specifically measure proteins' dopamination. More than 6,000 dopamination sites were quantified. Half-maximal inhibitory concentration values for 63 hypersensitive sites were measured. Among them, hypersensitive dopamination of two cysteines in microtubule-associated protein Tau was biochemically validated and functionally characterized to prevent Tau's amyloid fibrillation and promote Tau-mediated assembly of microtubules. In addition, endogenous dopamination of Tau in mouse brain was detected through targeted mass spectrometry analysis. Our study not only provides a global portrait of dopamination but also discovers a protective role of DA in regulating the function of Tau, which will enhance our understanding of the physiological and pathological functions of DA in human brain.

Alzheimer's disease (AD) is primarily caused by oxidative stress, hyperphosphorylated τ-protein aggregation, and amyloid-β deposition. Changes in dopaminergic and serotoninergic neurotransmitter pathways are linked to certain symptoms of AD. Derivatives of bicyclic and tricyclic cyclohepta[b]thiophene were developed to identify new potential candidates as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors for the treatment of AD. All synthesized compounds exhibited AChE inhibition with IC50 values below 15 μM, while all compounds exhibited BChE inhibition with IC50 values below 25 μM. Compounds 9 and 12 exhibited AChE inhibitory activities with IC50 values of 0.51 μM and 0.55 μM, respectively. Compounds 5 and 9 demonstrated excellent inhibitory activity against BChE with IC50 values of 2.9 μM and 2.48 μM, respectively. Compounds 9, 13, and 14 were found to be the most active in terms of the decrease in the escape latency time, with values comparable to that of Donepezil. Compounds 10, 11, and 12 exhibited promising effects on learning and memory. Compounds 5, 10, 11, and 12 exhibited promising SAP values of 70.67 %, 71.5 %, 74.33 % and 73.83 %, respectively. Other biomarkers were evaluated in rat brains including TAC, MDA, SOD, BDNF, IL-β and TNF-α. Fundamental features of ADMET have been computed in-silico for synthesized compounds. Molecular docking was performed to confirm the binding of the novel compounds to the targets.

Hyperphosphorylation and aggregation of the microtubule-associated tau protein, which plays a critical role in many neurodegenerative diseases (ie, tauopathies) including Alzheimer's disease (AD), are known to be regulated by a variety of environmental factors including temperature. In this study we evaluated the effects of FDA-approved poly (D,L-lactide-co-glycolic) acid (PLGA) nanoparticles, which can inhibit amyloid-β aggregation/toxicity in cellular/animal models of AD, on temperature-dependent aggregation of 0N4R tau isoforms in vitro.

We have used a variety of biophysical (Thioflavin T kinetics, dynamic light scattering and asymmetric-flow field-flow fractionation), structural (fluorescence imaging and transmission electron microscopy) and biochemical (Filter-trap assay and detection of soluble protein) approaches, to evaluate the effects of native PLGA nanoparticles on the temperature-dependent tau aggregation.

Our results show that the aggregation propensity of 0N4R tau increases significantly in a dose-dependent manner with a rise in temperature from 27°C to 40°C, as measured by lag time and aggregation rate. Additionally, the aggregation of 2N4R tau increases in a dose-dependent manner. Native PLGA significantly inhibits tau aggregation at all temperatures in a concentration-dependent manner, possibly by interacting with the aggregation-prone hydrophobic hexapeptide motifs of tau. Additionally, native PLGA is able to trigger disassembly of preformed 0N4R tau aggregates as a function of temperature from 27°C to 40°C.

These results, taken together, suggest that native PLGA nanoparticles can not only attenuate temperature-dependent tau aggregation but also promote disassembly of preformed aggregates, which increased with a rise of temperature. Given the evidence that temperature can influence tau pathology, we believe that native PLGA may have a unique potential to regulate tau abnormalities associated with AD-related pathology.

Murine models of Alzheimer's disease (AD) are crucial for elucidating disease mechanisms but have limitations in fully representing AD molecular complexities. Here we present the comprehensive, age-dependent brain proteome and phosphoproteome across multiple mouse models of amyloidosis. We identified shared pathways by integrating with human metadata and prioritized components by multi-omics analysis. Collectively, two commonly used models (5xFAD and APP-KI) replicate 30% of the human protein alterations; additional genetic incorporation of tau and splicing pathologies increases this similarity to 42%. We dissected the proteome-transcriptome inconsistency in AD and 5xFAD mouse brains, revealing that inconsistent proteins are enriched within amyloid plaque microenvironment (amyloidome). Our analysis of the 5xFAD proteome turnover demonstrates that amyloid formation delays the degradation of amyloidome components, including Aβ-binding proteins and autophagy/lysosomal proteins. Our proteomic strategy defines shared AD pathways, identifies potential targets, and underscores that protein turnover contributes to proteome-transcriptome discrepancies during AD progression.

This review highlights the crucial role of neuroelectrophysiology in illuminating the mechanisms underlying Alzheimer's disease (AD) pathogenesis and progression, emphasizing its potential to inform the development of effective treatments. Electrophysiological techniques provide unparalleled precision in exploring the intricate networks affected by AD, offering insights into the synaptic dysfunction, network alterations, and oscillatory abnormalities that characterize the disease. We discuss a range of electrophysiological methods, from non-invasive clinical techniques like electroencephalography and magnetoencephalography to invasive recordings in animal models. By drawing on findings from these studies, we demonstrate how electrophysiological research has deepened our understanding of AD-related network disruptions, paving the way for targeted therapeutic interventions. Moreover, we underscore the potential of electrophysiological modalities to play a pivotal role in evaluating treatment efficacy. Integrating electrophysiological data with clinical neuroimaging and longitudinal studies holds promise for a more comprehensive understanding of AD, enabling early detection and the development of personalized treatment strategies. This expanded research landscape offers new avenues for unraveling the complexities of AD and advancing therapeutic approaches.

Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disease. However, definitive diagnosis could be delayed by up to 12 months due to the lack of specific and sensitive biomarkers for ALS. In our study, conducted for the first time on a large cohort of ALS patients (n = 100) within the Russian population, we assessed key biomarkers of neurodegenerative pathology, including β-amyloids (Aβ40 and Aβ42) and tau proteins (Tau-total and Tau-p181), as well as other pathogenetically relevant, promising biomarkers such as FGF-21, Kallikrein-6 (KLK-6), NCAM-1, Neurogranin (NRGN), TDP-43, Apolipoprotein E4, Clusterin (Apo J), Complement Factor H, Fetuin-A, α2-Macroglobulin, Apo AI, Apo CIII, Apo E, Complement C3, GDNF, sRAGE, and S100B protein. Significant differences between the ALS patients and the control group were observed for Aβ40 (p = 0.044), Aβ42 (p < 0.001), FGF-21 (p < 0.001), Tau-total (p = 0.001), Tau-p181 (p = 0.014), Clusterin (p < 0.001), Complement C3 (p = 0.001), and S100B (p = 0.024). A significant direct correlation was found between the ALSFRS-R score and concentrations of Aβ40 and Aβ42. Changes in the complement system (Complement C3 and Complement Factor H) were identified, highlighting critical role of neuroinflammatory processes in ALS pathogenesis. Additionally, increased levels of FGF-21 were observed in the patients with the bulbar onset of ALS. Significant increase in the concentration of the chaperone protein clusterin in the patients with rapid disease progression suggests its potential as a prognostic biomarker for motor neuron disease. Furthermore, its role in maintaining proteostasis could provide novel therapeutic targets.

Amyloid fibrils represent a pathological state of protein polymer that is closely associated with various neurodegenerative diseases. Polysaccharides have a prominent role in recognizing amyloid fibrils and mediating their pathogenicity. However, the mechanism underlying the amyloid-polysaccharide interaction remains elusive. We also do not know its impact on the structure and pathology of formed fibrils. Here, we used cryo-electron microscopy to analyze the atomic structures of mature α-synuclein (α-syn) fibrils upon binding with polymeric heparin and heparin-like oligosaccharides. The fibril structure, including the helical twist and conformation of α-syn, changed over time upon the binding of heparin but not oligosaccharides. The sulfation pattern and numbers of saccharide units are important for the binding. Similarly, negatively charged biopolymers typically interact with amyloid fibrils, including tau and various α-syn polymorphs, leading to alterations in their conformation. Moreover, we show that heparin-like oligosaccharides can not only block neuronal uptake and propagation of formed α-syn fibrils but also inhibit α-syn fibrillation. This work demonstrates a distinctive activity of heparin and biopolymers in remodeling amyloid fibrils and suggests the pharmaceutical potential of heparin-like oligosaccharides.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by memory impairment that significantly interferes with daily life. Therapeutic options for AD that substantively modify disease progression remain a critical unmet need. In this regard, the gut microbiota is crucial in maintaining human health by regulating metabolism and immune responses, and increasing evidence suggests that probiotics, particularly beneficial bacteria, can enhance memory and cognitive functions. Recent studies have highlighted the positive effects of Bifidobacterium breve MCC1274 (B. breve MCC1274) on individuals with mild cognitive impairment (MCI) and schizophrenia. Additionally, oral supplementation with B. breve MCC1274 has been shown to effectively prevent memory decline in AppNL-G-F mice. In relation to Alzheimer's pathology, oral supplementation with B. breve MCC1274 has been found to reduce amyloid-β (Aβ) accumulation and tau phosphorylation in both AppNL-G-F and wild-type (WT) mice. It also decreases microglial activation and increases levels of synaptic proteins. In this review, we examine the beneficial effects of B. breve MCC1274 on AD, exploring potential mechanisms of action and how this probiotic strain may aid in preventing or treating the disease. Furthermore, we discuss the broader implications of B. breve MCC1274 for improving overall host health and provide insights into future research directions for this promising probiotic therapy.

Alzheimer's disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies and infectious agents, with herpes simplex virus 1 (HSV-1) being a leading candidate. Our investigation, using metagenomics, mass spectrometry, western blotting, and decrowding expansion pathology, detects HSV-1-associated proteins in human brain samples. Expression of the herpesvirus protein ICP27 increases with AD severity and strongly colocalizes with p-tau but not with Aβ. Modeling in human brain organoids shows that HSV-1 infection elevates tau phosphorylation. Notably, p-tau reduces ICP27 expression and markedly decreases post-infection neuronal death from 64% to 7%. This modeling prompts investigation into the cGAS-STING-TBK1 pathway products, nuclear factor (NF)-κB and IRF-3, which colocalizes with ICP27 and p-tau in AD. Furthermore, experimental activation of STING enhances tau phosphorylation, while TBK1 inhibition prevents it. Together, these findings suggest that tau phosphorylation acts as an innate immune response in AD, driven by cGAS-STING.

Lingguizhugan decoction (LGZG) has been reported to treat Alzheimer's disease (AD) by anti-inflammatory and transporting amyloid-β (Aβ).

Using APP/PS1 transgenic mice as in vivo model and gave LGZG decoction by oral gavage. Using Aβ25-35-induced SH-SY5Y cells as in vitro model and then added LGZG medicated serum (LMS) to observe the regulatory effect of LGZG on AD autophagy-related pathways. Morris water maze (MWM) was used to evaluate the mice's learning and memory ability. Mice's hippocampus tissue sections were stained immunohistochemically to observe hippocampal Aβ deposition. Transmission electron microscopy monitored autophagosomes and autolysosomes. Western blot analysis measured protein expression levels of beclin-1, p62 and light chain 3II (LC3 II) and mTOR signaling. Results: LGZG could greatly improve learning and memory ability of APP/PS1 mice, and enhance autophagy in vitro and in vivo. LGZG increased the levels of beclin-1 and LC3 II and decreased the levels of p62.

LGZG enhanced autophagy and showed therapeutic potential in AD by inhibiting mTOR/p70s6K signaling.

Alzheimer's disease (AD) is well known among the elderly and has a profound impact on both patients and their families. Increasing research indicates that AD is a systemic disease, with a strong connection to cardiovascular disease. They share common genetic factors, such as mutations in the presenilin (PS1 and PS2) and the apolipoprotein E (APOE) genes. Cardiovascular conditions can lead to reduced cerebral blood flow and increased oxidative stress. These factors contribute to the accumulation of Aβ plaques and the formation of abnormal tau protein tangles, which are both key pathological features of AD. Additionally, Aβ deposits and abnormal protein responses have been observed in cardiomyocytes as well as in peripheral tissues. The toxic Aβ deposition intensifies damage to the microvascular structure associated with blood-brain barrier disruption and the initiation of neuroinflammation, which may accelerate the onset of neurocognitive deficits and cardiovascular dysfunction. Thus, we discuss the main mechanisms linking AD and cardiac dysfunction to enhance our understanding of these conditions. Ultimately, insights into the brain-heart axis may help us develop effective treatment strategies in the future.

JOURNAL/nrgr/04.03/01300535-202501000-00033/figure1/v/2024-05-14T021156Z/r/image-tiff The E3 ubiquitin ligase, carboxyl terminus of heat shock protein 70 (Hsp70) interacting protein (CHIP), also functions as a co-chaperone and plays a crucial role in the protein quality control system. In this study, we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer's disease. We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain. CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests, reduced amyloid-β plaques, and decreased the expression of both amyloid-β and phosphorylated tau. CHIP also alleviated the concentration of microglia and astrocytes around plaques. In APP/PS1 mice of a younger age, CHIP overexpression promoted an increase in ADAM10 expression and inhibited β-site APP cleaving enzyme 1, insulin degrading enzyme, and neprilysin expression. Levels of HSP70 and HSP40, which have functional relevance to CHIP, were also increased. Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated, which may also reflect a potential mechanism for the neuroprotective effect of CHIP. Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice. Indeed, overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) often coexists with cerebrovascular diseases. However, the impact of cerebrovascular diseases such as stroke on AD pathology remains poorly understood.

This study examines the correlation between cerebrovascular diseases and AD pathology. The research was carried out using clinical and neuropathological data collected from the National Alzheimer's Coordinating Center (NACC) database and an animal model in which bilateral common carotid artery stenosis surgery was performed, following the injection of tau seeds into the brains of wild-type mice.

Analysis of the NACC database suggests that clinical stroke history and lacunar infarcts are associated with lower neurofibrillary tangle pathology. An animal model demonstrates that chronic cerebral hypoperfusion reduces tau pathology, which was observed in not only neurons but also astrocytes, microglia, and oligodendrocytes. Furthermore, we found that astrocytes and microglia were activated in response to tau pathology and chronic cerebral hypoperfusion. Additionally, cerebral hypoperfusion increased a lysosomal enzyme, cathepsin D.

These data together indicate that cerebral hypoperfusion reduces tau accumulation likely through an increase in microglial phagocytic activity towards tau and an elevation in degradation through cathepsin D. This study contributes to understanding the relationship between tau pathology and cerebrovascular diseases in older people with multimorbidity.