• Alzheimer's disease
• Dementia
• Diabetes
• Insulin resistance
• Metabolic syndrome
• Obesity

• GLUT4 trafficking
• TBC1D4/AS160
• WNK
• anxiety
• insulin signaling
• memory
• neuronal glucose metabolism
• sortilin

• K99 AG075161 NIA NIH HHS
• R37 NS114516 NINDS NIH HHS
• S10 OD021684 NIH HHS
• P30 CA142543 NCI NIH HHS
• R01 HL147661 NHLBI NIH HHS

• Alzheimer’s disease
• Morris water maze
• arterial pressure telemetry
• insulin signaling
• metabolic syndrome

• Animals
• Rats
• Male
• Metabolic Syndrome/complications
• Leptin/metabolism
• Rats, Zucker
• Phosphatidylinositol 3-Kinases/metabolism
• Receptors, Leptin/metabolism
• Obesity
• Hypertension
• Insulin
• Prosencephalon
• Disease Models, Animal
• Hippocampus/metabolism

• R01 HL132568 NHLBI NIH HHS
• JES Edwards Foundation
• Robert G. Summerfield Foundation
• HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
• University of North Texas (UNT)

• LC-MS
• NMR
• fa/fa rats
• genetic obesity
• metabolomics

• 20-00546S Czech Science Foundation
• 61388971 Czech Academy of Sciences
• 61388963 Czech Academy of Sciences
• 67985823 Czech Academy of Sciences

Recent evidence links brain insulin resistance with neurodegenerative diseases, where hyperphosphorylated tau protein contributes to neuronal cell death. In the present study, we aimed to evaluate if d‐pinitol inositol, which acts as an insulin sensitizer, affects the phosphorylation status of tau protein.

We studied the pharmacological effect of d‐pinitol on insulin signalling and tau phosphorylation in the hippocampus of Wistar and Zucker rats. To this end, we evaluated by western blotting the Akt pathway and its downstream proteins as being one of the main insulin‐mediator pathways. Also, we explored the functional status of additional kinases phosphorylating tau, including PKA, ERK1/2, AMPK and CDK5. We utilized the 3xTg mouse model as a control for tauopathy, since it carries tau mutations that promote phosphorylation and aggregation.

Surprisingly, we discovered that oral d‐pinitol treatment lowered tau phosphorylation significantly, but not through the expected kinase GSK‐3 regulation. An extensive search for additional kinases phosphorylating tau revealed that this effect was mediated through a mechanism dependent on the reduction of the activity of the CDK5, affecting both its p35 and p25 subunits. This effect disappeared in leptin‐deficient Zucker rats, uncovering that the association of leptin deficiency, obesity, dyslipidaemia and hyperinsulinaemia abrogates d‐pinitol actions on tau phosphorylation. The 3xTg mice confirmed d‐pinitol effectiveness in a genetic AD‐tauopathy.

The present findings suggest that d‐pinitol, by regulating CDK5 activity through a decrease of CDK5R1, is a potential drug for developing treatments for neurological disorders such as tauopathies.

• d-pinitol
• Akt
• CDK5
• insulin
• tau phosphorylation
• tauopathy

Anorexigenic palmitoylated prolactin-releasing peptide (palm¹¹-PrRP) is able to act centrally after peripheral administration in rat and mouse models of obesity, type 2 diabetes mellitus and/or neurodegeneration. Functional leptin and intact leptin signaling pathways are necessary for the body weight reducing and glucose tolerance improving effect of palm¹¹-PrRP. We have previously shown that palm¹¹-PrRP31 had glucose-lowering properties but not anti-obesity effect in Koletsky rats with leptin signaling disturbances, so improvements in glucose metabolism appear to be completely independent of leptin signaling. The purpose of this study was to describe relationship between metabolic and neurodegenerative pathologies and explore if palm¹¹-PrRP31 could ameliorate them in obese fa/fa rat model with leptin signaling disruption.

The fa/fa rats and their age-matched lean controls at the age 32 weeks were used for this study. The rats were infused for 2 months with saline or palm¹¹-PrRP31 (n = 7–8 per group) at a dose of 5 mg/kg per day using Alzet osmotic pumps. During the dosing period food intake and body weight were monitored. At the end of experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected and arterial blood pressure was measured. Then, markers of leptin and insulin signaling, Tau phosphorylation, neuroinflammation, and synaptogenesis were measured by western blotting and immunohistochemistry.

Fa/fa rats developed obesity, mild glucose intolerance, and peripheral insulin resistance but not hypertension while palm¹¹-PrRP31 treatment neither lowered body weight nor attenuated glucose tolerance but ameliorated leptin and insulin signaling and synaptogenesis in hippocampus.

We demonstrated that palm¹¹-PrRP31 had neuroprotective features without anti-obesity and glucose lowering effects in fa/fa rats. This data suggest that this analog has the potential to exert neuroprotective effect despite of leptin signaling disturbances in this rat model.

• Leptin
• Neurofibrillary pathology
• Tau protein
• Transgenic rat

• Alzheimer Disease/pathology
• Animals
• Disease Models, Animal
• Humans
• Leptin/metabolism
• Obesity
• Rats
• Tauopathies
• tau Proteins/metabolism

• VEGA 2/0160/20; 2/0076/18; APVV-17-0668; APVV-15-0229; BrainTest, s.r.o. Agentúra Ministerstva Školstva, Vedy, Výskumu a Športu SR

Background: The intricate relationship between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) suggests that insulin is involved in modulating AD-related proteins. Alpha-lipoic acid (ALA) can improve insulin resistance (IR) in diabetic rats. However, the role of ALA in alleviating the cognitive decline of T2DM is not yet clear. This study examined the ameliorative effect of ALA on cognitive impairment, cerebral IR, and synaptic plasticity abnormalities in high-fat diet (HFD) plus streptozotocin (STZ) induced diabetic rats.

Methods: The HFD/STZ-induced T2DM male Wistar rats were orally administered with ALA (50, 100, or 200 mg/kg BW) once a day for 13 weeks. Abilities of cognition were measured with a passive avoidance test and Morris water maze. Specimens of blood and brain were collected for biochemical analysis after the rats were sacrificed. Western blotting was used to determine protein expressions in the hippocampus and cortex in the insulin signaling pathways, long-term potentiation (LTP), and synaptic plasticity-related protein expressions.

Results: Alpha-lipoic acid improved hyperinsulinemia and the higher levels of free fatty acids of the T2DM rats. Behavioral experiments showed that the administration of ALA improved cognitive impairment in HFD/STZ-induced T2DM rats. ALA ameliorated insulin-related pathway proteins [phosphoinositide 3-kinase (PI3K), phospho-protein kinase B (pAkt)/Akt, and insulin-degrading enzyme (IDE)] and the LTP pathway, as well as synaptic plasticity proteins (calmodulin-dependent protein kinase II, cyclic AMP response element-binding protein, and postsynaptic density protein-95) of the cerebral cortex or hippocampus in HFD/STZ-induced T2DM rats.

Conclusion: Our findings suggested that ALA may ameliorate cognition impairment via alleviating cerebral IR improvement and cerebral synaptic plasticity in diabetic rats.

• Alzheimer’s disease
• cerebral insulin signaling
• long-term potentiation
• type 2 diabetes
• α-lipoic acid

Obesity leads to low-grade inflammation in the adipose tissue and liver and neuroinflammation in the brain. Obesity-induced insulin resistance (IR) and neuroinflammation seem to intensify neurodegeneration including Alzheimer’s disease. In this study, the impact of high-fat (HF) diet-induced obesity on potential neuroinflammation and peripheral IR was tested separately in males and females of THY-Tau22 mice, a model of tau pathology expressing mutated human tau protein.

Three-, 7-, and 11-month-old THY-Tau22 and wild-type males and females were tested for mobility, anxiety-like behavior, and short-term spatial memory in open-field and Y-maze tests. Plasma insulin, free fatty acid, cholesterol, and leptin were evaluated with commercial assays. Liver was stained with hematoxylin and eosin for histology. Brain sections were 3′,3′-diaminobenzidine (DAB) and/or fluorescently detected for ionized calcium-binding adapter molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and tau phosphorylated at T231 (pTau (T231)), and analyzed. Insulin signaling cascade, pTau, extracellular signal-regulated kinase 1/2 (ERK1/2), and protein phosphatase 2A (PP2A) were quantified by western blotting of hippocampi of 11-month-old mice. Data are mean ± SEM and were subjected to Mann-Whitney t test within age and sex and mixed-effects analysis and Bonferroni’s post hoc test for age comparison.

Increased age most potently decreased mobility and increased anxiety in all mice. THY-Tau22 males showed impaired short-term spatial memory. HF diet increased body, fat, and liver weights and peripheral IR. HF diet-fed THY-Tau22 males showed massive Iba1+ microgliosis and GFAP+ astrocytosis in the hippocampus and amygdala. Activated astrocytes colocalized with pTau (T231) in THY-Tau22, although no significant difference in hippocampal tau phosphorylation was observed between 11-month-old HF and standard diet-fed THY-Tau22 mice. Eleven-month-old THY-Tau22 females, but not males, on both diets showed decreased synaptic and postsynaptic plasticity.

Significant sex differences in neurodegenerative signs were found in THY-Tau22. Impaired short-term spatial memory was observed in 11-month-old THY-tau22 males but not females, which corresponded to increased neuroinflammation colocalized with pTau(T231) in the hippocampi and amygdalae of THY-Tau22 males. A robust decrease in synaptic and postsynaptic plasticity was observed in 11-month-old females but not males. HF diet caused peripheral but not central IR in mice of both sexes.

The online version contains supplementary material available at 10.1186/s12974-021-02190-3.

• Alzheimer’s disease
• Neuroinflammation
• Obesity
• Peripheral insulin resistance
• Sex differences
• THY-Tau22 mouse

The dbPTM (http://dbPTM.mbc.nctu.edu.tw/) has been maintained for over 10 years with the aim to provide functional and structural analyses for post-translational modifications (PTMs). In this update, dbPTM not only integrates more experimentally validated PTMs from available databases and through manual curation of literature but also provides PTM-disease associations based on non-synonymous single nucleotide polymorphisms (nsSNPs). The high-throughput deep sequencing technology has led to a surge in the data generated through analysis of association between SNPs and diseases, both in terms of growth amount and scope. This update thus integrated disease-associated nsSNPs from dbSNP based on genome-wide association studies. The PTM substrate sites located at a specified distance in terms of the amino acids encoded from nsSNPs were deemed to have an association with the involved diseases. In recent years, increasing evidence for crosstalk between PTMs has been reported. Although mass spectrometry-based proteomics has substantially improved our knowledge about substrate site specificity of single PTMs, the fact that the crosstalk of combinatorial PTMs may act in concert with the regulation of protein function and activity is neglected. Because of the relatively limited information about concurrent frequency and functional relevance of PTM crosstalk, in this update, the PTM sites neighboring other PTM sites in a specified window length were subjected to motif discovery and functional enrichment analysis. This update highlights the current challenges in PTM crosstalk investigation and breaks the bottleneck of how proteomics may contribute to understanding PTM codes, revealing the next level of data complexity and proteomic limitation in prospective PTM research.

• diet
• gut dysbiosis
• hyperinsulinemia
• inflammation
• insulin resistance
• memory

• Animals
• Blood-Brain Barrier/physiopathology
• Cognitive Dysfunction/etiology
• Cognitive Dysfunction/physiopathology
• Endothelium, Vascular/physiopathology
• Humans
• Obesity/complications
• Obesity/physiopathology

• R25 GM113278 NIGMS NIH HHS
• R25 GM072643 NIGMS NIH HHS
• U24 NS107232 NINDS NIH HHS
• R01 NS099595 NINDS NIH HHS
• T32 HL007260 NHLBI NIH HHS

• AD gene therapy
• AD molecular targets
• AD therapeutics
• Tau therapies
• alzheimer´s disease
• amyloid beta therapies

• Autophagy
• Cholesterol metabolism
• Protein homeostasis
• Synaptic function

Obesity, caused by a high-fat diet (HFD), leads to insulin resistance, which is a precursor of diabetes and a risk factor for impaired cognitive function, dementia, and brain diseases, such as Alzheimer’s disease. Physical exercise has positive effects on obesity and brain functions. We investigated whether the decline in cognitive function caused by a HFD could be improved through exercise by examining insulin signaling pathways and neuroplasticity in the hippocampus. Four-week-old C57BL/6 male mice were fed a HFD or a regular diet for 20 weeks, followed by 12 weeks of treadmill exercise. To ascertain the effects of treadmill exercise on impaired cognitive function caused by obesity, the present study implemented behavioral testing (Morris water maze, step-down). Moreover, insulin-signaling and neuroplasticity were measured in the hippocampus and dentate gyrus. Our results demonstrated that HFD-fed obesity-induced insulin resistance was improved by exercise. In addition, the HFD group showed a decrease in insulin signaling and neuroplasticity in the hippocampus and the dentate gyrus and increased cognitive function impairment, which were reversed by physical exercise. Overall, our findings indicate that physical exercise may act as a non-pharmacologic method that protects against cognitive dysfunction caused by obesity by improving hippocampal insulin signaling and neuroplasticity.

• cognitive function
• exercise
• hippocampus
• insulin signaling
• neuroplasticity
• obesity

• Animal Feed
• Animals
• Cognition
• Diet/veterinary
• Diet, High-Fat/adverse effects
• Hippocampus/cytology
• Hippocampus/physiology
• Insulin/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Neuronal Plasticity/drug effects
• Obesity/chemically induced
• Physical Conditioning, Animal
• Signal Transduction/drug effects
• Signal Transduction/physiology

• Blood glucose
• Cognition
• Diet
• Exercise
• Impaired glucose tolerance
• Inflammation
• Insulin resistance
• Metabolic risk
• Metabolism
• Neurodegeneration
• Obesity
• Oxidative stress
• Type 2 diabetes

• GLP-1
• hippocampus
• learning
• memory
• neurogenesis
• obesity
• plasticity
• vagus nerve

• F31 DK116558 NIDDK NIH HHS
• R01 DK104897 NIDDK NIH HHS
• R01 DK118402 NIDDK NIH HHS

• Alzheimer’s disease pathology
• anorexigenic neuropeptides
• experimental rodent models
• leptin

• Alzheimer Disease/metabolism
• Alzheimer Disease/prevention & control
• Animals
• Appetite Depressants/metabolism
• Appetite Depressants/pharmacology
• Disease Models, Animal
• Energy Metabolism/drug effects
• Homeostasis/drug effects
• Humans
• Leptin/metabolism
• Neuroprotective Agents/pharmacology
• Oligopeptides/metabolism
• Oligopeptides/pharmacology
• Pyrrolidonecarboxylic Acid/analogs & derivatives
• Pyrrolidonecarboxylic Acid/metabolism
• Pyrrolidonecarboxylic Acid/pharmacology

Alzheimer’s disease (AD) is a neurodegenerative disorder, most cases of which lack a clear causative event. This has made the disease difficult to characterize and, thus, diagnose. Although some cases are genetically linked, there are many diseases and lifestyle factors that can lead to an increased risk of developing AD, including traumatic brain injury, diabetes, hypertension, obesity, and other metabolic syndromes, in addition to aging. Identifying common factors and trends between these conditions could enhance our understanding of AD and lead to the development of more effective treatments. Although the immune system is one of the body’s key defense mechanisms, chronic inflammation has been increasingly linked with several age-related diseases. Moreover, it is now well accepted that chronic inflammation has an important role in the onset and progression of AD. In this review, the different inflammatory signals associated with AD and its risk factors will be outlined to demonstrate how chronic inflammation may be influencing individual susceptibility to AD. Our goal is to bring attention to potential shared signals presented by the immune system during different conditions that could lead to the development of successful treatments.

• APOE4
• Aging
• Alzheimer’s disease
• CD33
• Diabetes
• Microglia
• Neuroinflammation
• Obesity
• TBI
• TREM2

• Alzheimer’s disease
• Cognitive deficits
• Monosodium glutamate
• Plasticity-related proteins
• Tau hyperphosphorylation

• Alzheimer's disease
• diabetes-induced dementia
• drug design
• natural products
• type 2 diabetes

A high-fat diet (HFD), one of the major factors contributing to metabolic syndrome, which is associated with an increased risk of neurodegenerative diseases, leads to insulin resistance and cognitive impairment. It is not known whether these alterations are improved with dietary intervention. To investigate the long-term impact of a HFD on hippocampal insulin signaling and memory, C57BL6 mice were placed into one of three groups based on the diet: a standard diet (control), a HFD, or a HFD for 16 weeks and then the standard diet for 8 weeks (HF₁₆). HFD-induced impairments in glucose tolerance and hippocampal insulin signaling occurred concurrently with deficits in both short- and long-term memory. Furthermore, these conditions were improved with dietary intervention; however, the HFD-induced decrease in insulin receptor expression in the hippocampus was not altered with dietary intervention. Our results demonstrate that memory deficits due to the consumption of a HFD at an early age are reversible.

• Aging
• Cognition
• Hippocampus
• Spatial memory
• Tau phosphorylation

• brain
• bromocryptine
• diabetes mellitus
• insulin
• leptin
• melanocortin
• metabolic syndrome
• neurodegeneration
• signaling systems
• treatment

• Alzheimer’s disease (AD)
• amyloid-β (Aβ)
• biomarkers
• tau protein
• β-site APP cleaving enzyme 1 (BACE1)