Alzheimer's Disease-related Protein Research Articles

A Cross-Sectional Study of Alzheimer-Related Proteins in Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine condition in women of reproductive age, and several risk factors found in PCOS are associated with an increased risk of Alzheimer's disease (AD). Proteins increased in AD have been reported to include fibronectin (FN) fragments 3 and 4 (FN1.3 and FN1.4, respectively) and ApoE. We hypothesized that Alzheimer-related proteins would be dysregulated in PCOS because of associated insulin resistance and obesity. In this comparative cross-sectional analysis, aptamer-based SomaScan proteomic analysis for the detection of plasma Alzheimer-related proteins was undertaken in a PCOS biobank of 143 women with PCOS and 97 control women. Amyloid precursor protein (APP) (p < 0.05) and amyloid P-component (APCS) (p < 0.001) were elevated in PCOS, while alpha-synuclein (SNCA) (p < 0.05) was reduced in PCOS. Associations with protective heat shock proteins (HSPs) showed that SNCA positively correlated with HSP90 (p < 0.0001) and HSP60 (p < 0.0001) in both the PCOS and control women. Correlations with markers of inflammation showed that APCS correlated with interleukin 6 (IL6) (p = 0.04), while Apolipoprotein (Apo) E3 correlated with TNF-alpha (p = 0.02). FN, FN1.3, FN1.4 and ApoE were all elevated significantly (p < 0.05). An AD-associated protein pattern with elevated FN, FN1.3, FN1.4 and ApoE was found in PCOS, in addition to elevated APP and reduced SNCA, which was the same as reported for type 2 diabetes (T2D) with, additionally, an elevation in APCS. With the AD biomarker pattern in PCOS being very similar to that in T2D, where there is an association between AD and T2D, this suggests that larger prospective cohort studies are needed in women with PCOS to determine if there is a causal association with AD.

Photo-Excited Dyes: Emerging Technique Against Tau Protein Aggregation.

Tau aggregates are considered a pathological hallmark of Alzheimer's disease. The screening of molecules against Tau aggregation is a novel strategy for Alzheimer's disease. The photo-excited molecules have proven to be effective as a therapeutic agent in several diseases. In recent studies, the photo-excited dyes showed an inhibitory effect on Alzheimer's disease-related Tau protein aggregation and toxicity. The present chapter deals with the effect of rose bengal on the aggregation of Tau. The in vitro studies carried out with the help of electron microscopy, ThS fluorescence, and circular dichroism suggested that RB attenuated the Tau aggregation under in vitro conditions, whereas PE-RB disaggregated the mature Tau fibrils. Photo-excited rose bengal and the classicalrose bengal induced a low degree of toxicity in cells. Thus, for the treatment of Alzheimer's disease, the rose bengal could be considered a potential molecule.

Alzheimer's Disease-Related Proteins Targeted by Secondary Metabolite Compounds from Streptomyces: A Scoping Review.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized as rapid and progressive cognitive decline affecting 26 million people worldwide. Although immunotherapies are ideal, its clinical safety and effectiveness are controversial, hence, treatments are still reliant on symptomatic medications. Concurrently, the Streptomyces genus has attracted attention given its pharmaceutically beneficial secondary metabolites to treat neurodegenerative diseases. To present secondary metabolites from Streptomyces sp. with regulatory effects on proteins and identified prospective target proteins for AD treatment. Research articles published between 2010 and 2021 were collected from five databases and 83 relevant research articles were identified. Post-screening, only 12 research articles on AD-related proteins were selected for further review. Bioinformatics analyses were performed through the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) network, PANTHER Go-Slim classification system (PANTHER17.0), and Kyoto Encyclopedia of Genes and Genomes (KEGG) Mapper. A total of 20 target proteins were identified from the 12 shortlisted articles. Amyloid-β, BACE1, Nrf-2, Beclin-1, and ATG5 were identified as the potential target proteins, given their role in initiating AD, mitigating neuroinflammation, and autophagy. Besides, 10 compounds from Streptomyces sp., including rapamycin, alborixin, enterocin, bonnevillamides D and E, caniferolide A, anhydroexfoliamycin, rhizolutin, streptocyclinone A and B, were identified to exhibit considerable regulatory effects on these target proteins. The review highlights several prospective target proteins that can be regulated through treatments with Streptomyces sp. compounds to prevent AD's early stages and progression. Further identification of Streptomyces sp. compounds with potential anti-AD properties is recommended.

Ameliorative effects of Dunaliella salina microalgae on nanoparticle (ZnO NPs)-induced toxicity in fish.

Dunaliella salina (D. salina) is a well-known microalga that contains considerable amounts of nutritious and medicinal bioactive components. This work studied the modulatory role of D. salina against zinc oxide nanoparticle (ZnO NPs)-induced neurotoxic effects in adult zebrafish. Fishes were subjected to 0.69mg L-1 (1/5th 96-h LC50) for 4weeks; then, fishes were supplemented with D. salina in the diet for 2weeks at two levels (15 and 30%). Exposure to ZnO NPs induced a significant increase in the levels of reactive oxygen species (ROS), hydrogen peroxide (H2O2), malondialdehyde (MDA), and 8-hydroxy-2-deoxyguanosine (8-OH-dG) while accompanied with downregulation of antioxidant genes in the brain of exposed fishes. Brain neurochemistry and enzyme activities were also altered following ZnO NP exposure. ZnO NPs significantly reduced the neurotransmitters and acetylcholinesterase (AchE) activity while increasing Alzheimer's disease-related proteins and inflammatory response via upregulation of tumor necrosis factor (TNF-α). Additionally, ZnO NPs increased the indices of brain's DNA oxidative damage, increasing brain tissue's metallothionein (MT) and zinc residues. ZnO NPs upregulated the transcription patterns of apoptosis-related genes (casp3 and p53). D. salina dietary co-supplementation with ZnO NPs alleviated the ZnO NPsZnO NP-induced neuro-oxidative damages by lowering the lipid, DNA damage, and inflammatory biomarkers. Besides, D. salina alleviating responses were linked with increasing the levels of the assessed antioxidants. Conclusively, D. salina dietary supplementation induced potential alleviating effects of the ZnO NP-induced neurotoxicity in adult zebrafish.

Identification of potential inhibitors against Alzheimer-related proteins in Cordyceps militaris ethanol extract: experimental evidence and computational analyses.

Laboratory experiments were carried out to identify the chemical composition of Cordyceps militaris and reveal the first evidence of their Alzheimer-related potential. Liquid chromatography-mass spectrometry analysis identified 21 bioactive compounds in the ethanol extract (1-21). High-performance liquid chromatography quantified the content of cordycepin (0.32%). Bioassays revealed the overall anti-Alzheimer potential of the extract against acetylcholinesterase (IC50 = 115.9 ± 11.16µgmL-1). Multi-platform computations were utilized to predict the biological inhibitory effects of its phytochemical components against Alzheimer-related protein structures: acetylcholinesterase (PDB-4EY7) and β-amyloid protein (PDB-2LMN). In particular, 7 is considered as a most effective inhibitor predicted by its chemical stability in dipole-based environments (ground state - 467.26302 a.u.; dipole moment 11.598 Debye), inhibitory effectiveness ( - 13.6kcalmol-1), polarized compatibility (polarizability 25.8 Å3; logP - 1.01), and brain penetrability (logBB - 0.244; logPS - 3.047). Besides, 3 is promising as a brain-penetrating agent (logBB - 0.257; logPS - 2.400). The results preliminarily suggest further experimental attempts to verify the pro-cognitive effects of l(-)-carnitine (7). The online version contains supplementary material available at 10.1007/s13205-023-03714-9.

Preventive Effect of Indian Gooseberry (Phyllanthus emblica L.) Fruit Extract on Cognitive Decline in High-Fat Diet (HFD)-Fed Rats.

Methylglyoxal (MG)-derived advanced glycation end products (AGEs) directly bind to the receptor for advanced glycation end products (RAGE), subsequently exacerbating obesity and obesity-induced cognitive decline. Indian gooseberry (Phyllanthus emblica L.) fruit has antiobesity properties. However, the underlying mechanism by which Indian gooseberry fruit prevents obesity-induced cognitive decline remains unclear. This study aims to investigate the preventive effect of a water extract of Indian gooseberry fruit (WEIG) and its bioactive compound gallic acid (GA) on the obesity-induced cognitive decline through MG suppression and gut microbiota modulation in high-fat diet (HFD)-fed rats. Trapping MG, WEIG, and GA significantly ameliorate fat accumulation in adipose tissue and learning and memory deficits. Mechanistically, WEIG and GA administration effectively reduces brain MG and AGE levels and subsequently reduces insulin resistance, inflammatory cytokines, MDA production, and Alzheimer's disease-related proteins, but increases both antioxidant enzyme activities and anti-inflammatory cytokine with inhibiting RAGE, MAPK, and NF-κB levels in HFD-fed rats. Additionally, WEIG and GA supplementation increases the relative abundances of Bacteroidetes, Gammaproteobacteria, and Parasutterella, which negatively correlate with MG, inflammatory cytokine, and Alzheimer's disease-related protein expressions. This novel finding provides a possible mechanism by which WEIG prevents obesity-induced cognitive decline through the gut-brain axis.

Apoptosis inhibitor attenuates cardiac ischemia/reperfusion injury‐induced amyloid beta aggregation and dendritic spine loss in rats

Recently, several studies have reported the incidence of cognitive impairments in patients with acute myocardial infarction and heart failure. Mechanistically, dendritic spine loss in hippocampus, due to oxidative stress/inflammation induced apoptosis, is proposed as one of responsible mechanisms underlying cognitive impairments. However, the effects of z-vad, which is an apoptosis inhibitor, on brain pathologies following cardiac ischemia/reperfusion (I/R) injury have never been investigated. We hypothesized that z-vad alleviates brain damage in rats with cardiac I/R injury by reducing apoptosis, mitochondrial oxidative stress, and inflammation. Fifty-four male rats were subjected to either sham (n=6/group) or cardiac I/R operation (n=48). Rats in cardiac I/R group were divided into 4 groups (n=6-12/group) including 1) vehicle, 2) low-dose of z-vad (L-z-vad; 1.65 mg/kg), medium-dose of z-vad (M-z-vad; 3.3 mg/kg), and high-dose of z-vad (H-z-vad; 6.6 mg/kg). Treatments were intravenously injected to the rats at 15 min before ischemia. Then, rats were subjected to left anterior descending coronary artery ligation induced myocardial ischemia for 30 min, followed by 120 min of reperfusion. At the end of protocol, rats were sacrificed, and the brain was used to determine mitochondrial oxidative stress, inflammation, cell death pathways, blood brain barrier (BBB), Alzheimer's disease related proteins, and dendritic spine density. Cardiac I/R injury led to BBB breakdown, increased brain mitochondrial oxidative stress and apoptosis, as well as amyloid beta aggregation, tau hyperphosphorylation, and subsequent dendritic spine loss. Treatment with M-z-vad and H-z-vad reduced dendritic spine loss, tau hyperphosphorylation, and Bax/Bcl2 ratio. Additionally, the reduction of dendritic spine density was lowered in M-z-vad than H-z-vad group, since only M-z-vad attenuated mitochondrial oxidative stress, inflammation, amyloid beta aggregation, and cleaved-caspase 3 protein expression. For L-z-vad, we found that this treatment regimen showed no benefit on brain pathologies following cardiac I/R injury, implying that low dose of z-vad may be insufficient to exert neuroprotection (Figure 1). Moreover, all doses of z-vad did not decrease BBB breakdown after cardiac I/R injury. Pretreatment with medium dose of apoptosis inhibitor prevented amyloid beta aggregation and dendritic spine loss against cardiac I/R injury, possibly through reductions of mitochondrial oxidative stress, inflammation, and apoptosis.

Acetylcholinesterase inhibitor provides neuroprotective effects against doxorubicin‐induced chemobrain

Chemobrain has recently been recognized as the most common neurological consequences following chemotherapy, particularly doxorubicin (Dox) treatment. In addition, the incidence of Alzheimer's disease (AD) increases in response to chemotherapy. Dox administration induced cognitive impairment via brain oxidative stress, neuroinflammation, mitochondrial dysfunction, cholinergic deficits, and cumulating neuronal apoptosis. Notably, donepezil (DPZ), an acetylcholinesterase inhibitor, has been proven to effectively attenuate various neuropathological conditions, particularly AD. However, the mechanistic insight regarding the protective effects of DPZ on cognition and brain pathologies in rats with doxorubicin-induced chemobrain has never been determined. Fifteen male Wistar rats were randomized to receive either a 0.9% normal saline solution (Control; n=5) or 3 mg/kg Dox for 6 doses via intraperitoneal injection. Then, Dox-treated rats were divided into 2 groups to receive either vehicle (Dox, n=5) or DPZ (5 mg/kg: Dox+DPZ; n=5) orally, starting at 1st day of Dox for a 30-day duration. After completion of the treatment paradigm, cognitive function was evaluated using the novel object location (NOL) task. The brains were obtained for further molecular investigation. Dox-treated rats exhibited impaired cognitive performance as presented by a decline in preference index in the NOL test. Loss of dendritic spines was observed following Dox treatment. Dox-treated rats showed brain mitochondrial dysfunction as indicated by increased mitochondrial reactive oxygen species (ROS) production (Figure 1) and imbalanced mitochondrial dynamics. Additionally, Dox induced neuroinflammation as demonstrated by increased TNF-α mRNA expression, together with enhanced microglial activation (Figure 1). Interestingly, Dox-treated rats developed potential amyloid lesions (Figure 1) and disrupted neurogenesis in the hippocampus which in turn led to neuronal cell death through both apoptosis and necroptosis. Strikingly, DPZ co-treatment completely restored cognitive function (Figure 1) by reducing dendritic spine loss, improving mitochondrial function, balancing mitochondrial dynamics, ameliorating neuroinflammation, decreasing Alzheimer's related proteins, preserving neurogenesis, and inhibiting apoptosis and necroptosis. These findings suggested that DPZ provided neuroprotection against Dox-induced chemobrain, which could be used for the therapeutic approach to prevent chemobrain in patients who received chemotherapy in the future.

Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells

The hippocampal-entorhinal system supports cognitive functions, has lifelong neurogenic capabilities in many species, and is selectively vulnerable to Alzheimer's disease. To investigate neurogenic potential and cellular diversity, we profiled single-nucleus transcriptomes in five hippocampal-entorhinal subregions in humans, macaques, and pigs. Integrated cross-species analysis revealed robust transcriptomic and histologic signatures of neurogenesis in the adult mouse, pig, and macaque but not humans. Doublecortin (DCX), a widely accepted marker of newly generated granule cells, was detected in diverse human neurons, but it did not define immature neuron populations. To explore species differences in cellular diversity and implications for disease, we characterized subregion-specific, transcriptomically defined cell types and transitional changes from the three-layered archicortex to the six-layered neocortex. Notably, METTL7B defined subregion-specific excitatory neurons and astrocytes in primates, associated with endoplasmic reticulum and lipid droplet proteins, including Alzheimer's disease-related proteins. This resource reveals cell-type- and species-specific properties shaping hippocampal-entorhinal neurogenesis and function.

Curiosity-Based Interventions Increase Everyday Functioning Score But Not Serum BDNF Levels in a Cohort of Healthy Older Adults.

An enriched environment is effective in stimulating learning and memory in animal models as well as in humans. Environmental enrichment increases brain-derived neurotrophic factor (BDNF) in aged rats and reduces levels of Alzheimer-related proteins in the blood, including amyloid-β (Aβ) peptides and misfolded toxic forms of tau. To address whether stimulation of curiosity, which is a form of enrichment, may provide a buffer against Alzheimer’s disease (AD), we measured levels of biomarkers associated with AD at baseline and after a 6-week intervention in older adults (>65 years of age) randomized to one of three different intervention conditions. Specifically, in this pilot study, we tested the effectiveness of a traditional, structured learning environment compared to a self-motivated learning environment designed to stimulate curiosity. There were no significant differences from baseline to post-intervention in any of the groups for Aβ42/Aβ40 ratio or t-tau (total-tau) plasma levels. Serum BDNF levels decreased significantly in the control group. Interestingly, individuals who had the lowest serum BDNF levels at baseline experienced significantly higher increases in BDNF over the course of the 6-week intervention compared to individuals with higher serum BDNF levels at baseline. As expected, older individuals had lower MoCA scores. Years of education correlated negatively with Aβ levels, suggesting a protective effect of education on levels of this toxic protein. ECog scores were negatively correlated with BDNF levels, suggesting that better performance on the ECog questionnaire was associated with higher BDNF levels. Collectively, these findings did not suggest that a 6-week cognitive training intervention focused on curiosity resulted in significant alterations in blood biomarkers but showed interesting correlations between cognitive scores and BDNF levels, further supporting the role of this trophic factor in brain health in older adults.

Rivastigmine attenuates the Alzheimer's disease related protein degradation and apoptotic neuronal death signalling.

Rivastigmine is a clinical drug for patients of Alzheimer's disease (AD) exerting its inhibitory effect on acetylcholinesterase activity however, its effect on other disease-related pathological mechanisms are not yet known. This study was conducted to evaluate the effect of rivastigmine on protein aggregation and degradation related mechanisms employing streptozotocin (STZ) induced experimental rat model. The known inhibitory effect of rivastigmine on cognition and acetylcholinesterase activity was observed in both cortex and hippocampus and further its effect on tau level, amyloid aggregation, biochemical alterations, endoplasmic reticulum (ER) stress, calcium homeostasis, proteasome activity and apoptosis was estimated. STZ administration in rat brain caused significant cognitive impairment, augmented acetylcholinesterase activity, tau phosphorylation and amyloid aggregation which were significantly inhibited with rivastigmine treatment. STZ also caused significant biochemical alterations which were attenuated with rivastigmine treatment. Since AD pathology is related to protein aggregation and we have found disease-related amyloid aggregation, further the investigation was done to decipher the ER functionality and apoptotic signalling. STZ caused significantly altered level of ER stress related markers (GRP78, GADD153 and caspase-12) which were significantly inhibited with rivastigmine treatment. Furthermore, the effect of rivastigmine was estimated on proteasome activity in both regions. Rivastigmine treatment significantly enhances the proteasome activity and may contributes in removal of amyloid aggregation. In conclusion, findings suggested that along with inhibitory effect of rivastigmine on acetylcholinesterase activity and up to some extent on cognition, it has significant effect on disease-related biochemical alterations, ER functionality, protein degradation machinery and neuronal apoptosis.

Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons.

The dependence of neurons on microtubule-based motors for the movement of lysosomes over long distances raises questions about adaptations that allow neurons to meet these demands. Recently, JIP3/MAPK8IP3, a neuronally enriched putative adaptor between lysosomes and motors, was identified as a critical regulator of axonal lysosome abundance. In this study, we establish a human induced pluripotent stem cell (iPSC)-derived neuron model for the investigation of axonal lysosome transport and maturation and show that loss of JIP3 results in the accumulation of axonal lysosomes and the Alzheimer’s disease–related amyloid precursor protein (APP)-derived Aβ42 peptide. We furthermore reveal an overlapping role of the homologous JIP4 gene in lysosome axonal transport. These results establish a cellular model for investigating the relationship between lysosome axonal transport and amyloidogenic APP processing and more broadly demonstrate the utility of human iPSC–derived neurons for the investigation of neuronal cell biology and pathology.

Participation of Amyloid and Tau Protein in Post-Ischemic Neurodegeneration of the Hippocampus of a Nature Identical to Alzheimer's Disease.

Recent evidence suggests that amyloid and tau protein are of vital importance in post-ischemic death of CA1 pyramidal neurons of the hippocampus. In this review, we summarize protein alterations associated with Alzheimer’s disease and their gene expression (amyloid protein precursor and tau protein) after cerebral ischemia, as well as their roles in post-ischemic hippocampus neurodegeneration. In recent years, multiple studies aimed to elucidate the post-ischemic processes in the development of hippocampus neurodegeneration. Their findings have revealed the dysregulation of genes for amyloid protein precursor, β-secretase, presenilin 1 and 2, tau protein, autophagy, mitophagy, and apoptosis identical in nature to Alzheimer’s disease. Herein, we present the latest data showing that amyloid and tau protein associated with Alzheimer’s disease and their genes play a key role in post-ischemic neurodegeneration of the hippocampus with subsequent development of dementia. Therefore, understanding the underlying process for the development of post-ischemic CA1 area neurodegeneration in the hippocampus in conjunction with Alzheimer’s disease-related proteins and genes will provide the most important therapeutic development goals to date.

Brain Ischemia as a Prelude to Alzheimer's Disease.

Transient ischemic brain injury causes massive neuronal death in the hippocampus of both humans and animals. This was accompanied by progressive atrophy of the hippocampus, brain cortex, and white matter lesions. Furthermore, it has been noted that neurodegenerative processes after an episode of ischemia-reperfusion in the brain can continue well-beyond the acute stage. Rarefaction of white matter was significantly increased in animals at 2 years following ischemia. Some rats that survived 2 years after ischemia developed severe brain atrophy with dementia. The profile of post-ischemic brain neurodegeneration shares a commonality with neurodegeneration in Alzheimer's disease. Furthermore, post-ischemic brain injury is associated with the deposition of folding proteins, such as amyloid and tau protein, in the intracellular and extracellular space. Recent studies on post-ischemic brain neurodegeneration have revealed the dysregulation of Alzheimer's disease-associated genes such as amyloid protein precursor, α-secretase, β-secretase, presenilin 1, presenilin 2, and tau protein. The latest data demonstrate that Alzheimer's disease-related proteins and their genes play a key role in the development of post-ischemic brain neurodegeneration with full-blown dementia in disease types such as Alzheimer's. Ongoing interest in the study of brain ischemia has provided evidence showing that ischemia may be involved in the development of the genotype and phenotype of Alzheimer's disease, suggesting that brain ischemia can be considered as a useful model for understanding the mechanisms responsible for the initiation of Alzheimer's disease.

Determining the Protein Stability of Alzheimer's Disease Protein, Amyloid Precursor Protein.

Determining protein thermal stability is integral in biomedical research. Here, with the use of two thermal stability assays, we show the melting temperature of amyloid precursor protein, an Alzheimer's disease related protein. The average melting temperature for amyloid precursor protein of 55.9°C was derived from differential scanning fluorometry (55.1 ± 0.3°C) and cellular thermal melt (56.7 ± 0.7°C). These experimental methods have significant application for Alzheimer's disease research including their use for amyloid precursor protein stability profiling and for the identification of additional binding partners to further elucidate novel protein functions.

Selective loss of cortical endothelial tight junction proteins during Alzheimer's disease progression.

While the accumulation and aggregation of amyloid-β and tau are central events in the pathogenesis of Alzheimer's disease, there is increasing evidence that cerebrovascular pathology is also abundant in Alzheimer's disease brains. In brain capillaries, endothelial cells are connected closely with one another through transmembrane tight junction proteins forming the blood-brain barrier. Because the blood-brain barrier tightly regulates the exchange of molecules between brain and blood and maintains brain homeostasis, its impairment is increasingly recognized as a critical factor contributing to Alzheimer's disease pathogenesis. However, the pathological relationship between blood-brain barrier properties and Alzheimer's disease progression in the human brain is not fully understood. In this study, we show that the loss of cortical tight junction proteins is a common event in Alzheimer's disease, and is correlated with synaptic degeneration. By quantifying the amounts of major tight junction proteins, claudin-5 and occludin, in 12 brain regions dissected from post-mortem brains of normal ageing (n = 10), pathological ageing (n = 14) and Alzheimer's disease patients (n = 19), we found that they were selectively decreased in cortical areas in Alzheimer's disease. Cortical tight junction proteins were decreased in association with the Braak neurofibrillary tangle stage. There was also a negative correlation between the amount of tight junction proteins and the amounts of insoluble Alzheimer's disease-related proteins, in particular amyloid-β40, in cortical areas. In addition, the amount of tight junction proteins in these areas correlated positively with those of synaptic markers. Thus, loss of cortical tight junction proteins in Alzheimer's disease is associated with insoluble amyloid-β40 and loss of synaptic markers. Importantly, the positive correlation between claudin-5 and synaptic markers, in particular synaptophysin, was present independent of insoluble amyloid-β40, amyloid-β42 and tau values, suggesting that loss of cortical tight junction proteins and synaptic degeneration is present, at least in part, independent of insoluble Alzheimer's disease-related proteins. Collectively, these results indicate that loss of tight junction proteins occurs predominantly in the neocortex during Alzheimer's disease progression. Further, our findings provide a neuropathological clue as to how endothelial tight junction pathology may contribute to Alzheimer's disease pathogenesis in both synergistic and additive manners to typical amyloid-β and tau pathologies.

Amyloid pathology in the brain after ischemia.

As the population is aging all over the world, the economic burden of ischemic brain injuries is constantly increasing. Human brain ischemia is one of the leading causes of premature death, significant morbidity and physical and mental disabilities, resulting in a lower quality of life and unusually high costs of health and social care. One of the most difficult problems associated with the pathology of the brain after ischemia is progressive dementia observed in people who survived the stroke. More recently, brain ischemia has been shown to elicit Alzheimer's disease neuropathologic change, possibly facilitating the development of dementia due to the amyloidogenic processing of Alzheimer's disease-related amyloid protein precursor into amyloid. The main purpose of this review is to present the development of Alzheimer's disease neuropathologic change in the brain after human and experimental ischemia, with a particular emphasis on proteins and genes involved in the amyloidogenic processing of the amyloid protein precursor to amyloid.

Mechanistic basis for the recognition of a misfolded protein by the molecular chaperone Hsp90.

The critical toxic species in over 40 human diseases are misfolded proteins. Their interaction with molecular chaperones such as Hsp90, which preferentially interacts with metastable proteins, is essential for the blocking of disease progression. Here we used nuclear magnetic resonance (NMR) spectroscopy to determine the three-dimensional structure of the misfolded cytotoxic monomer of the amyloidogenic human protein transthyretin, which is characterized by the release of the C-terminal β-strand and perturbations of the A-B loop. The misfolded transthyretin monomer, but not the wild-type protein, binds to human Hsp90. In the bound state, the Hsp90 dimer predominantly populates an open conformation, and transthyretin retains its globular structure. The interaction surface for the transthyretin monomer comprises the N-terminal and middle domains of Hsp90 and overlaps with that of the Alzheimer's-disease-related protein tau. Taken together, the data suggest that Hsp90 uses a mechanism for the recognition of aggregation-prone proteins that is largely distinct from those of other Hsp90 clients.

Tau and β-Amyloid Are Associated with Medial Temporal Lobe Structure, Function, and Memory Encoding in Normal Aging.

Normal aging is associated with a decline in episodic memory and also with aggregation of the β-amyloid (Aβ) and tau proteins and atrophy of medial temporal lobe (MTL) structures crucial to memory formation. Although some evidence suggests that Aβ is associated with aberrant neural activity, the relationships among these two aggregated proteins, neural function, and brain structure are poorly understood. Using in vivo human Aβ and tau imaging, we demonstrate that increased Aβ and tau are both associated with aberrant fMRI activity in the MTL during memory encoding in cognitively normal older adults. This pathological neural activity was in turn associated with worse memory performance and atrophy within the MTL. A mediation analysis revealed that the relationship with regional atrophy was explained by MTL tau. These findings broaden the concept of cognitive aging to include evidence of Alzheimer's disease-related protein aggregation as an underlying mechanism of age-related memory impairment.SIGNIFICANCE STATEMENT Alterations in episodic memory and the accumulation of Alzheimer's pathology are common in cognitively normal older adults. However, evidence of pathological effects on episodic memory has largely been limited to β-amyloid (Aβ). Because Aβ and tau often cooccur in older adults, previous research offers an incomplete understanding of the relationship between pathology and episodic memory. With the recent development of in vivo tau PET radiotracers, we show that Aβ and tau are associated with different aspects of memory encoding, leading to aberrant neural activity that is behaviorally detrimental. In addition, our results provide evidence linking Aβ- and tau-associated neural dysfunction to brain atrophy.

Neuroprotective effect of the Chinese medicine Tiantai No. 1 and its molecular mechanism in the senescence-accelerated mouse prone 8.

Tiantai No. 1, a Chinese medicine predominantly composed of powdered Rhizoma Gastrodiae, Radix Ginseng, and Ginkgo leaf at a ratio of 2:1:2 and dissolved in pure water, is neuroprotective in animal models of various cognitive disorders, but its molecular mechanism remains unclear. We administered Tiantai No. 1 intragastrically to senescence-accelerated mouse prone 8 (SAMP8) mice (a model of Alzheimer's disease) at doses of 50, 100 or 150 mg/kg per day for 8 weeks and evaluated their behavior in the Morris water maze and expression of Alzheimer's disease-related proteins in the brain. Tiantai No. 1 shortened the escape latency in the water maze training trials, and increased swimming time in the target quadrant during the spatial probe test, indicating that Tiantai No. 1 improved learning and memory in SAMP8 mice. Immunohistochemistry revealed that Tiantai No. 1 restored the proliferation potential of Ki67-positive cells in the hippocampus. In addition, mice that had received Tiantai No. 1 had fewer astrocytes, and less accumulation of amyloid-beta and phosphorylated tau. These results suggest that Tiantai No. 1 is neuroprotective in the SAMP8 mouse model of Alzheimer's disease and acts by restoring neuronal number and proliferation potential in the hippocampus, decreasing astrocyte infiltration, and reducing the accumulation of amyloid-beta and phosphorylated tau.