Presence Of Senile Plaques Research Articles

Bioinformatic analysis of the SPs and NFTs proteomes unravel putative biomarker candidates for Alzheimer's disease.

Aging is the main risk factor for the appearance of age-related neurodegenerative diseases, including Alzheimer's disease (AD). AD is the most common form of dementia, characterized by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the main histopathological hallmarks in AD brains. The core of these deposits are predominantly amyloid fibrils in SPs and hyperphosphorylated Tau protein in NFTs, but other molecular components can be found associated with these pathological lesions. Herein, an extensive literature review was carried out to obtain the SPs and NFTs proteomes, followed by a bioinformatic analysis and further putative biomarker validation. For SPs, 857 proteins were recovered, and, for NFTs, 627 proteins of which 375 occur in both groups and represent the common proteome. Gene Ontology (GO) enrichment analysis permitted the identification of biological processes and the molecular functions most associated with these lesions. Analysis of the SPs and NFTs common proteins unraveled pathways and molecular targets linking both histopathological events. Further, validation of a putative phosphotarget arising from the in silico analysis was performed in serum-derived extracellular vesicles from AD patients. This bioinformatic approach contributed to the identification of putative molecular targets, valuable for AD diagnostic or therapeutic intervention.

Differential Binding and Conformational Dynamics of Tau Microtubule-Binding Repeats with a Preformed Amyloid-β Fibril Seed.

Both senile plaques formed by amyloid-β (Aβ) and neurofibrillary tangles (NFTs) comprised of tau are pathological hallmarks of Alzheimer's disease (AD). The accumulation of NFTs better correlates with the loss of cognitive function than senile plaques, but NFTs are rarely observed without the presence of senile plaques. Hence, cross-seeding of tau by preformed Aβ amyloid fibril seeds has been proposed to drive the aggregation of tau and exacerbate AD progression, but the molecular mechanism remains unknown. Here, we first identified cross-interaction hotspots between Aβ and tau using atomistic discrete molecular dynamics simulations (DMD) and confirmed the critical role of the four microtubule-binding repeats of tau (R1-R4) in the cross-interaction with Aβ. We further investigated the binding structure and dynamics of each tau repeat with a preformed Aβ fibril seed. Specifically, R1 and R3 preferred to bind the Aβ fibril lateral surface instead of the elongation end. In contrast, R2 and R4 had higher binding propensities to the fibril elongation end than the lateral surface, enhancing β-sheet content by forming hydrogen bonds with the exposed hydrogen bond donors and acceptors. Together, our results suggest that the four repeats play distinct roles in driving the binding of tau to different surfaces of an Aβ fibril seed. Binding of tau to the lateral surface of Aβ fibril can increase the local concentration, while the binding to the elongation surface promotes β-sheet formation, both of which reduce the free energy barrier for tau aggregation nucleation and subsequent fibrillization.

Differential binding dynamics of four microtubule-binding repeats of tau with an amyloid-β fibril seed.

Both senile plaques formed by amyloid-beta (Aβ) and neurofibrillary tangles comprised of tau are hallmarks of Alzheimer's disease (AD). The accumulation of neurofibrillary tangles better correlates with the loss of cognitive function than senile plaques, but neurofibrillary tangles are rarely observed without the presence of senile plaques. Hence, cross-seeding of tau by preformed Aβ amyloid fibril seeds has been proposed to drive the aggregation of tau and exacerbate AD progression, but the molecular mechanism remains poorly understood. Herein, we identified cross-interaction hotspots between Aβ and tau using atomistic discrete molecular dynamics simulations (DMD) and confirmed the critical role of the four microtubule-binding repeats of tau (R1-R4) in the cross-interaction with Aβ. We further investigated the binding structure and dynamics of each tau repeat with a preformed Aβ fibril seed. Specifically, R1 and R3 preferred to bind the lateral instead of elongation surfaces of the fibril, preserving similar secondary structures as in the solution. In contrast, R2 and R4 had higher binding propensities to the elongation than lateral surfaces, adopting β-sheet structures by forming hydrogen bonds with the exposed hydrogen bond donors and acceptors. Together, our results suggest that four MTBD repeats play distinct roles in driving the binding of tau to two different surfaces of an Aβ fibril seed. The binding of tau to the lateral surface of Aβ fibril can increase the local concentration, while the binding in the elongation surface promotes β-sheet formation, both of which reduce the free energy barrier for tau aggregation nucleation and subsequent fibrillization. Our computational study offers molecular insight into the experimentally observed cross-seeding of Tau aggregation by pre-formed Aβ fibril seeds and helps better understand the pathological synergy of Aβ and tau aggregation in the etiology of AD.

Modulations of bioactive lipids and their receptors in postmortem Alzheimer's disease brains.

Analyses of brain samples from Alzheimer's disease (AD) patients may be expected to help us improve our understanding of the pathogenesis of AD. Bioactive lipids, including sphingolipids, glycerophospholipids, and eicosanoids/related mediators have been demonstrated to exert potent physiological actions and to be involved in the pathogenesis of various human diseases. In this cross-sectional study, we attempted to elucidate the associations of these bioactive lipids with the pathogenesis/pathology of AD through postmortem studies of human brains. We measured the levels of glycerophospholipids, sphingolipids, and eicosanoids/related mediators in the brains of patients with AD (AD brains), patients with Cerad score B (Cerad-b brains), and control subjects (control brains), using a liquid chromatography-mass spectrometry method; we also measured the mRNA levels of specific receptors for these bioactive lipids in the same brain specimens. The levels of several species of sphingomyelins and ceramides were higher in the Cerad-b and AD brains. Levels of several species of lysophosphatidic acids (LPAs), lysophosphatidylcholine, lysophosphatidylserine, lysophosphatidylethanolamine (LPE), lysophosphatidylinositol, phosphatidylcholine, phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol, and phosphatidylglycerol were especially high in the Cerad-b brains, while those of lysophosphatidylglycerol (LPG) were especially high in the AD brains. Several eicosanoids, including metabolites of prostaglandin E2, oxylipins, metabolites of epoxide, and metabolites of DHA and EPA, such as resolvins, were also modulated in the AD brains. Among the lipid mediators, the levels of S1P2, S1P5, LPA1, LPA2, LPA6, P2Y10, GPR174, EP1, DP1, DP2, IP, FP, and TXA2r were lower in the AD and/or Cerad-b brains. The brain levels of ceramides, LPC, LPI, PE, and PS showed strong positive correlations with the Aβ contents, while those of LPG showed rather strong positive correlations with the presence of senile plaques and neurofibrillary tangles. A discriminant analysis revealed that LPG is especially important for AD and the LPE/PE axis is important for Cerad-b. Comprehensive lipidomics, together with the measurement of lipid receptor expression levels provided novel evidence for the associations of bioactive lipids with AD, which is expected to facilitate future translational research and reverse translational research.

Screening of Alzheimer's Disease With Multiwavelength Stokes Polarimetry in a Mouse Model.

The minimum histological criterion for the diagnostics of Alzheimer's disease (AD) in tissue is the presence of senile plaques and neurofibrillary tangles in specific brain locations. The routine procedure of morphological analysis implies time-consuming and laborious steps including sectioning and staining of formalin-fixed paraffin-embedded (FFPE) tissue. We developed a multispectral Stokes polarimetric imaging approach that allows characterization of FFPE brain tissue samples to discern the stages of AD progression without sectioning and staining the tissue. The Stokes polarimetry approach is highly sensitive to structural alterations of brain tissue, particularly to the changes in light scattering and birefringence. We present the results of the label-free non-destructive screening of FFPE mouse brain tissue and show several polarization metrics that demonstrate statistically significant differences for tissues at different stages of AD.

Flavonoids: The Innocuous Agents Offering Protection against Alzheimer's Disease Through Modulation of Proinflammatory and Apoptotic Pathways.

Beginning from mild cognitive impairment in patients suffering from Alzheimer's disease (AD), dementia sets in with the progress of the disease. The pathological changes in the brain begin fifteen to twenty years before AD related dementia develops. Presence of senile plaques and neurofibrillary tangles are considered the hallmarks of AD brain. Chronic inflammation resulting from the disruption of the equilibrium between anti-inflammatory and pro-inflammatory signalling emerges as another important feature of AD and also other neurodegenerative diseases. Substantial studies demonstrate that this sustained immune response in the brain is associated with neuronal loss, along with facilitation and aggravation of Aβ and NFT pathologies. Although it is well accepted that neuroinflammation and oxidative stress have both detrimental and beneficial influences on the brain tissues, the involvement of microglia and astrocytes in the onset and progress of the neurodegenerative process in AD is becoming increasingly recognized. Although the cause of neuronal loss is known to be apoptosis, the mechanism of promotion of neuronal death remains undisclosed. Controlling the activation of the resident immune cells and/or the excessive production of pro-inflammatory and pro-oxidant factors could be effective as therapeutics. Among the phytonutrients, the neuroprotective role of flavonoids is beyond doubt. This review is an exploration of the literature on the role of flavonoids in these aspects. Flavonoids are not only effective in ameliorating the adverse consequences of oxidative stress but also impede the development of late onset Alzheimer's disease by modulating affected signalling pathways and boosting signalling crosstalk.

How non-rapid eye movement sleep and Alzheimer pathology are linked.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by the presence of senile plaques and neurofibrillary tangles. Research attempts to identify characteristic factors that are associated with the presence of the AD pathology on the one hand and that increase the risk of developing AD on the other. Changes in non-rapid eye movement (NREM) sleep may meet both requirements for various reasons. First, NREM-sleep is important for optimal memory function. In addition, studies report that the presence of AD pathology is associated with NREM-sleep changes. Finally, more and more results appear to suggest that sleep problems are not only a symptom of AD but can also increase the risk of AD. Several of these studies suggest that it is primarily a lack of NREM-sleep that is responsible for this increased risk. However, the majority investigated sleep only through subjective reporting, as a result of which NREM-sleep could not be analyzed separately. The aim of this literature study is therefore to present the results of the studies that relate the AD pathology and NREM-sleep (registered by electroencephalography). Furthermore, we try to evaluate whether NREM-sleep analysis could be used to support the diagnosis of AD and whether NREM-sleep deficiency could be a causal factor in the development of AD.

Non-Drug Treatment Methods Used in Alzheimer Patients

Alzheimer hastalığı, hipokampus, serebral korteks ve subkortikal alanlarda senil plaklar ve nörofibriler düğümlerin varlığı ile karakterize en sık görülen nörodejeneratif hastalıktır. Hastalığın erken aşamaları klasik olarak bellekteki zayıflama ile ilişkilidir. Hastalığın erken evresinde bireyler kelime bulmakta, yeni insanların isimlerini hatırlamakta ve sosyal/iş görevlerinde zorluk yaşamaktadırlar. Beraberinde son günlerde okuduğu yazıyı unutma ve nesneleri yanlış yerleştirme gibi sorunlar görülebilmektedir. Hastalık ilerledikçe orta evrede önemli olayları veya kişisel anıları unutmak, sosyal geri çekilme, adres veya telefon numaralarını hatırlayamama, zaman ve yer oryantasyonunda bozulma, mevsime/ortama uygun kıyafet seçememe, uyku düzeni değişiklikleri, gezinme veya kaybolma riski, kişilik veya davranış değişiklikleri (şüphe, dürtüsellik, sanrılar ve tekrarlayan davranışlar) görülmektedir. Alzheimer hastalığının neden olduğu bu sorunların sona erdirilmesi için erken tanı, tedavi ve özellikle de önlenmesine yönelik çeşitli yaklaşımlara gereksinim vardır. Teknolojinin de ilerlemesiyle dünyada ve ülkemizde çalışmaların artmasına rağmen hastalığın önlenmesi ve kesin tedavisi henüz mümkün olmamaktadır. Ancak Alzheimer hastalığına sahip yaşlı bireylerin günlük yaşam aktivitelerine katılımı ve yaşam kalitesinin artırılabilmesi için ilaç tedavisinin yanı sıra özellikle hastalığın belirtilerini azaltmakta ilaç dışı yöntemler de uygulanmaktadır. 
 Bu derleme, farmakolojik tedavinin yanı sıra Alzheimer hastalarının semptomlarını azaltmak ve yaşam kalitesini artırmak için kullanılabilecek geleneksel ve destekleyici yöntemlerin hemşireler ve diğer sağlık profesyonellerine yol göstermesini amaçlamaktadır.

Leptin enhances adult neurogenesis and reduces pathological features in a transgenic mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common dementia worldwide and is characterized by the presence of senile plaques by amyloid-beta (Aβ) and neurofibrillary tangles of hyperphosphorylated Tau protein. These changes lead to progressive neuronal degeneration and dysfunction, resulting in severe brain atrophy and cognitive deficits. With the discovery that neurogenesis persists in the adult mammalian brain, including brain regions affected by AD, studies of the use of neural stem cells (NSCs) for the treatment of neurodegenerative diseases to repair or prevent neuronal cell loss have increased. Here we demonstrate that leptin administration increases the neurogenic process in the dentate gyrus of the hippocampus as well as in the subventricular zone of lateral ventricles of adult and aged mice. Chronic treatment with leptin increased NSCs proliferation with significant effects on proliferation and differentiation of newborn cells. The expression of the long form of the leptin receptor, LepRb, was detected in the neurogenic niches by reverse qPCR and immunohistochemistry. Moreover, leptin modulated astrogliosis, microglial cell number and the formation of senile plaques. Additionally, leptin led to attenuation of Aβ-induced neurodegeneration and superoxide anion production as revealed by Fluoro-Jade B and dihydroethidium staining. Our study contributes to the understanding of the effects of leptin in the brain that may lead to the development of new therapies to treat Alzheimer’s disease.

Targeting Pathological Amyloid Aggregates with Conformation-Sensitive Antibodies.

The pathogenesis of Alzheimer's disease (AD) is not directly caused by the presence of senile plaques but rather by the detrimental effects exerted on neuronal cells by toxic soluble oligomers. Such species are formed early during the aggregation process of the Aβ1-42 peptide or can be released from mature fibrils. Nowadays, efficient tools for an early diagnosis, as well as pharmaceutical treatments targeting the harmful agents in samples of AD patients, are still missing. By integrating in vitro immunochemical assay with in vivo neuronal models of toxicity, we aim to understand and target the principles that drive toxicity in AD. We evaluated the specificity and sensitivity of A11 and OC conformational antibodies to target a range of pathologically relevant amyloid conformers and rescue their cytotoxic effects in neuronal culture models using a number of cellular readouts. We demonstrated the peculiar ability of conformational antibodies to label pathologically relevant Aβ1-42 oligomers and fibrils and to prevent their detrimental effects on neuronal cells. Our results substantially improve our knowledge on the role of toxic assemblies in neurodegenerative diseases, thus suggesting new and more effective diagnostic and therapeutic tools for AD.

Resveratrol in Alzheimer's disease: a review of pathophysiology and therapeutic potential.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive and irreversible loss of cognitive function. The presence of senile plaques is one of the pathological markers of the disease and is associated with the onset of neuroinflammatory mechanisms. The exact pathophysiology of AD has not been completely understood, and there are no curative therapies yet. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenol that is noted for its antioxidant and anti-inflammatory properties. To review the role of resveratrol in the pathophysiological aspects of AD. This study carried out a literature review using PubMed/Medline, Virtual Health Library (VHL), Web of Sciences, SCOPUS and the Cochrane Library databases. Original research articles, describing both in vitro and in vivo experiments, published between 2008 and 2018, were included. We identified 667 articles, of which 619 were excluded because they were repeated or did not follow the inclusion criteria. The present study includes the remaining 48 articles. Resveratrol demonstrates beneficial and protective effects in AD models and seems to provide a promising therapeutic alternative. Although resveratrol appears to mitigate some pathophysiological aspects of AD, further studies are needed to prove the safety and efficacy of this compound in humans.

Microglia and Wnt Pathways: Prospects for Inflammation in Alzheimer's Disease.

Alzheimer’s disease (AD) has been a major health issue for more than one century since it was first reported in 1906. As one of the most common neurodegenerative diseases, AD is characterized by the presence of senile plaques and neurofibrillary tangles (NFTs) in the affected brain area. Microglia are the major regulators of neuroinflammation in the brain, and neuroinflammation has become recognized as the core pathophysiological process of various neurodegenerative diseases. In the central nervous system (CNS), microglia play a dual role in AD development. For one thing, they degrade amyloid β (Aβ) to resist its deposition; for another, microglia release pro-inflammatory and inflammatory factors, contributing to neuroinflammation as well as the spreading of Aβ and tau pathology. Wnt pathways are important regulators of cell fate and cell activities. The dysregulation of Wnt pathways is responsible for both abnormal tau phosphorylation and synaptic loss in AD. Recent studies have also confirmed the regulatory effect of Wnt signaling on microglial inflammation. Thus, the study of microglia, Wnt pathways, and their possible interactions may open up a new direction for understanding the mechanisms of neuroinflammation in AD. In this review, we summarize the functions of microglia and Wnt pathways and their roles in AD in order to provide new ideas for understanding the pathogenesis of AD.

Novel Anti-Alzheimer's Therapeutic Molecules Targeting Amyloid Precursor Protein Processing.

Alzheimer's disease (AD) is the most common cause of dementia among older people, and the prevalence of this disease is estimated to rise quickly in the upcoming years. Unfortunately, almost all of the drug candidates tested for AD until now have failed to exhibit any efficacy. Henceforth, there is an increased necessity to avert and/or slow down the advancement of AD. It is known that one of the major pathological characteristics of AD is the presence of senile plaques (SPs) in the brain. These SPs are composed of aggregated amyloid beta (Aβ), derived from the amyloid precursor protein (APP). Pharmaceutical companies have conducted a number of studies in order to identify safe and effective anti-Aβ drugs to combat AD. It is known that α-, β-, and γ-secretases are the three proteases that are involved in APP processing. Furthermore, there is a growing interest in these proteases, as they have a contribution to the modulation and production of Aβ. It has been observed that small compounds can be used to target these important proteases. Indeed, these compounds must satisfy the common strict requirements of a drug candidate targeted for brain penetration and selectivity toward different proteases. In this article, we have focused on the auspicious molecules which are under development for targeting APP-processing enzymes. We have also presented several anti-AD molecules targeting Aβ accumulation and phosphorylation signaling in APP processing. This review highlights the structure-activity relationship and other physicochemical features of several pharmacological candidates in order to successfully develop new anti-AD drugs.

Enhanced amyloid-β generation by γ-secretase complex in DRM microdomains with reduced cholesterol levels.

A neuropathologic hallmark of Alzheimer's disease (AD) is the presence of senile plaques that contain neurotoxic amyloid-β protein (Aβ) species, which are generated by the cleavage of amyloid β-protein precursor by secretases such as the γ-secretase complex, preferentially located in detergent-resistant membrane (DRM) regions and comprising endoproteolysed amino- and carboxy-terminal fragments of presenilin, nicastrin, anterior pharynx defective 1 and presenilin enhancer 2. Whereas some of familial AD patients harbor causative PSEN mutations that lead to more generation of neurotoxic Aβ42, the contribution of Aβ generation to sporadic/late-onset AD remains unclear. We found that the carboxy-terminal fragment of presenilin 1 was redistributed from DRM regions to detergent-soluble membrane (non-DRM) regions in brain tissue samples from individuals with sporadic AD. DRM fractions from AD brain sample had the ability to generate significantly more Aβ and had a lower cholesterol content than DRM fractions from non-demented control subjects. We further demonstrated that lowering the cholesterol content of DRM regions from cultured cells contributed to the redistribution of γ-secretase components and Aβ production. Taken together, the present analyses suggest that the lowered cholesterol content in DRM regions may be a cause of sporadic/late-onset AD by enhancing overall Aβ generation.

Histidine 131 in presenilin 1 is the pH-sensitive residue that causes the increase in Aβ42 level in acidic pH

Alzheimer disease (AD) is the most common neurodegenerative disease worldwide. The pathological hallmark of AD is the presence of senile plaques in the brain, which are accumulations of amyloid-β peptide (Aβ) ending at the 42nd residue (i.e. Aβ42), which is produced through multistep cleavage by γ-secretase. Thus, methods to regulate γ-secretase activity to attenuate the production of Aβ42 are in urgent demand towards the development of treatments for AD. We and others have demonstrated that γ-secretase activity is affected by its localization and ambient environment. In particular, an increase in Aβ42 production is correlated with the intracellular transport of γ-secretase and endosomal maturation-dependent luminal acidification. In this study, we focused on the mechanism by which γ-secretase affects Aβ42 production together with alterations in pH. Histidine is known to function as a pH sensor in many proteins, to regulate their activities through the protonation state of the imidazole side chain. Among the histidines facing the luminal side of presenilin (PS) 1, which is the catalytic subunit of γ-secretase, point mutations at H131 had no effect on the Aβ42 production ratio in an acidic environment. We also observed an increase in Aβ42 ratio when histidine was introduced into N137 of PS2, which is the corresponding residue of H131 in PS1. These results indicated that H131 serves as the pH sensor in PS1, which contains γ-secretase, to regulate Aβ42 production depending on the luminal pH. Our findings provide new insights into therapeutic strategies for AD targeting endosomes or the intracellular transport of γ-secretase.

Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer\u2019s disease-related dysregulation

BackgroundTrisomy 21 (T21) is associated with intellectual disability that ranges from mild to profound with an average intellectual quotient of around 50. Furthermore, T21 patients have a high risk of developing Alzheimer’s disease (AD) early in life, characterized by the presence of senile plaques of amyloid protein and neurofibrillary tangles, leading to neuronal loss and cognitive decline. We postulate that epigenetic factors contribute to the observed variability in intellectual disability, as well as at the level of neurodegeneration seen in T21 individuals.Materials and MethodsA genome-wide DNA methylation study was performed using Illumina Infinium® MethylationEPIC BeadChips on whole blood DNA of 3 male T21 patients with low IQ, 8 T21 patients with high IQ (4 males and 4 females), and 21 age- and sex-matched control samples (12 males and 9 females) in order to determine whether DNA methylation alterations could help explain variation in cognitive impairment between individuals with T21. In view of the increased risk of developing AD in T21 individuals, we additionally investigated the T21-associated sites in published blood DNA methylation data from the AgeCoDe cohort (German study on Ageing, Cognition, and Dementia). AgeCoDe represents a prospective longitudinal study including non-demented individuals at baseline of which a part develops AD dementia at follow-up.ResultsTwo thousand seven hundred sixteen differentially methylated sites and regions discriminating T21 and healthy individuals were identified. In the T21 high and low IQ comparison, a single CpG located in the promoter of PELI1 was differentially methylated after multiple testing adjustment. For the same contrast, 69 differentially methylated regions were identified. Performing a targeted association analysis for the significant T21-associated CpG sites in the AgeCoDe cohort, we found that 9 showed significant methylation differences related to AD dementia, including one in the ADAM10 gene. This gene has previously been shown to play a role in the prevention of amyloid plaque formation in the brain.ConclusionThe differentially methylated regions may help understand the interaction between methylation alterations and cognitive function. In addition, ADAM10 might be a valuable blood-based biomarker for at least the early detection of AD.

TDP-43 inhibitory peptide alleviates neurodegeneration and memory loss in an APP transgenic mouse model for Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized clinically by progressive decline in cognitive function and neuropathologically by the presence of senile plaques and neuronal loss in the brain. While current drugs for AD are always employed as symptomatic therapies with variable benefits, there is no treatment to delay its progression or halt neurodegeneration. TAR DNA-binding protein 43 (TDP-43) proteinopathy has increasingly been implicated as a prominent histopathological feature of AD and related dementias. Our recent studies have implicated mitochondria as critical targets of TDP-43 neurotoxicity. Here, we demonstrate that the suppression of mitochondrial-associated TDP-43 protects against neuronal loss and behavioral deficits in 5XFAD transgenic mice recapitulating AD-related phenotypes. In AD patients and 5XFAD mice, the level of TDP-43 is increased in mitochondria, and TDP-43 highly co-localizes with mitochondria in brain neurons exhibiting TDP-43 proteinopathy. Chronic administration of a TDP-43 mitochondrial localization inhibitory peptide, PM1, significantly alleviates TDP-43 proteinopathy, mitochondrial abnormalities, microgliosis and even neuronal loss without effect on amyloid plaque load in 12-month-old 5XFAD mice well after the onset of symptoms. Additionally, PM1 also improves the cognitive and motor function in 12-month-old 5XFAD mice and completely prevents the onset of mild cognitive impairment in 6-month-old 5XFAD mice. These data indicate that mitochondria-associated TDP-43 is likely involved in AD pathogenesis and that the inhibitor of mitochondria-associated TDP-43 may be a valuable drug to treat underlying AD.

Effects of experimental intracerebral ventricular injection of amyloid beta peptide (1-42) aggregates on daily rhythms of Aβ-degrading enzymes in the hippocampus: Relevance to Alzheimer's disease pathophysiology

One of the main pathological features in the Alzheimer disease (AD) is the presence of senile plaques, primarily composed of Aβ peptide aggregates, in cortex and hippocampus. AD late onset, which constitutes 90% of cases, could be mainly attributable to deficiencies in the clearance of the Aß peptide. Here we show that expression of Aβ-degrading enzymes varies on a daily basis in the hippocampus. Interestingly, an intracerebroventricular injection of Aβ aggregates modified temporal patterns of Aβ-degrading proteases, as well as clock proteins (BMAL1 and RORα) and antioxidant enzymes (CAT and GPx) daily rhythms. Our findings showed that the increase of Aβ leads to the alteration of the enzymes involved in the clearance, and, consequently, to an increase of oxidative stress and alteration of the cellular redox state, affecting the functioning of the endogenous clock and daily rhythms of BMAL1, RORα and their target genes, in this disease.

Regulation of AβPP Glycosylation Modification and Roles of Glycosylation on AβPP Cleavage in Alzheimer's Disease.

The presence of senile plaques in the gray matter of the brain is one of the major pathologic features of Alzheimer's disease (AD), and amyloid-β (Aβ) is the main component of extracellular deposits of the senile plaques. Aβ derives from amyloid-β precursor protein (AβPP) cleaved by β-secretase (BACE1) and γ-secretase, and the abnormal cleavage of AβPP is an important event leading to overproduction and aggregation of Aβ species. After translation, AβPP undergoes post-translational modifications (PTMs) including glycosylation and phosphorylation in the endoplasmic reticulum (ER) and Golgi apparatus, and these modifications play an important role in regulating the cleavage of this protein. In this Review, we summarize research progress on the modification of glycosylation, especially O-GlcNAcylation and mucin-type O-linked glycosylation (also known as O-GalNAcylation), on the regulation of AβPP cleavage and on the influence of AβPP's glycosylation in the pathogenesis of AD.

The Wnt/β-catenin signaling pathway affects the distribution of cytoskeletal proteins in Aβ treated PC12 cells.

Alzheimer's disease is pathologically characterized by the presence of senile plaques and neurofibrillary tangles in the central nervous system. Amyloid β-protein is toxic to neurons and induces phosphorylation of Tau protein, which accumulates in paired helical filaments and leads to the formation of neurofibrillary tangles. This study is focused on the Wnt/β-catenin pathway influence on Tau phosphorylation and the distribution of microtubules and neurofilaments in adrenal pheochromocytoma cells. It was found that neurofilament heavy polypeptide and microtubule-associated protein-2 aggregated after treatment with Aβ₁₋₄₂. Treatment with Wnt5a reduced this aggregation, while Dickkopf-1 treatment promoted microtubule and neurofilament aggregation. Furthermore, Tau phosphorylation at Ser396, Ser422, and Ser199 was significantly reduced after Wnt5a treatment, whereas Dickkopf-1 increased the level of phosphorylation. These results suggest that the Wnt/β-catenin pathway influences the distribution of microtubules and neurofilaments, possibly by modulating the phosphorylation of Tau protein in adrenal pheochromocytoma cells.