Sleep Disturbance: An Early Sign of Alzheimer’s Disease

Alzheimer's disease(AD)is a progressive neurodegenerative disorder associated with cognitive impairment in older adults.The accumulation of insoluble forms of amyloid-β(Aβ)in plaques in extracellular spaces and the aggregation of hyperphosphorylated microtubule-associated protein tau in neurofibrillary tangles in neurons are considered to be central pathological features of A D[1,2].     

More is Needed before Alzheimer's Disease can be Conquered

<正>German Neurologist Alois Alzheimer first reported the autopsy results of a fifty year old female patient named Auguste Deter in 1907.The patient presented with classic cognitive and behavioral disorder.The autopsy results showed two abnormal pathological changes:neurofibrillary tangles(NFTs)and senile plaques(SPs).In1924 Divery found that SPs consisted of amyloid using Congo red staining.In 1984,Glenner and Wong purified     

Streptozotocin induced Alzheimer’s disease like changes and the underlying neural degeneration and regeneration mechanism

<正>Alzheimer’s disease(AD)is a neurodegenerative disorder which is remarkably characterized by pathological hallmarks that include neurofibrillary tangles,neuronal loss extracellular senile plaques containing aggregated amyloid beta(Aβ),and neurofibrillary tangles composed of the hyperphosphorylated form of the microtubule protein tau.It is the most common form of dementia which is characterized by severe neurodegenerative changes such as loss of neurons and synapses in brain(Kamat et al.,2014).Several wellknown mutations that lead to early-onset familial AD exist.However,these circumstances only reason for a few percentages of total AD cases.     

The use of localized proteomics to identify the drivers of Alzheimer's disease pathogenesis

<正>Alzheimer’s disease(AD)is broadly defined by dementia and the presence of specific neuropathological features in the brain(amyloid plaques,neurofibrillary tangles(NFTs)and congophilic amyloid angiopathy).However,the rate of disease progression,type of cognitive impairment,and extent of neuropathology vary widely in patients with AD(Murray et al.,2011).Why this occurs is still unknown,but     

Administration of pre/probiotics with conventional drug treatment in Alzheimer's disease

正Alzheimer's disease(AD) is a neurodegenerative disease with long preclinical phase, typically followed by a slow decline in memory, thinking and reasoning abilities. The underlying pathological processes are not yet fully elucidated, although two main disease hallmarks have been associated with AD pathology: amyloid beta species and neurofibrillary tangles. The plaques are deposits of a protein fragment     

Potential preventive disease-modifying pharmacological strategies to delay late onset Alzheimer's disease

Alzheimer's disease(AD)is a progressive neurodegenerative disease that was histopathologically characterized in the brain by the presence of extracellular senile plaques made of amyloid β peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated Tau protein.Over the years,AD has been classified in two subgroups:early onset or familial AD and late onset or sporadic AD.On the one hand,familial AD has been described to be the result of genetic mutations that cause,in some cases,for the overproduction of amyloid β.On the other,the cause of late onset or sporadic AD is still unclear even though several hypotheses have been proposed to explain the process of severe and progressive memory and cognitive loss.In the present review,some of the current hypotheses that try to explain the origin of late onset or sporadic AD have been summarized.Also,their potential implication in the development of new drugs for the presymptomatic treatment of late onset or sporadic AD has been considered.     

p38-MAPK and CDK5,signaling pathways in neuroinflammation:a potential therapeutic intervention in Alzheimer's disease?

<正>Alzheimer’s disease(AD),the most common type of dementia,affects millions of people worldwide,putting a significant strain on healthcare infrastructure and societal resources.AD is characte rized by the build-up of amyloid-beta(Aβ)plaques and neurofibrillary to ngles containing hyperphosphorylated tau protein.These pathological features cause neuroinflammation,     

淀粉样前体蛋白胞内域的功能和机制

Alzheimer's disease (AD),a degenerative neurological disorder,is the most common form of dementia among older people,whose symptoms include gradual memory loss,cognitive impairments and deterioration of language skills.Amyloid precursor protein (APP) is cleaved by serials of secretases and generates Aβ,sAPPα/β and APP intracellular domain (AICD).Aβ forms amyloid plaques,together with neurofibrillary tangles (NFTs) which is comprised with hyperphosphorylated tau,are hallmarks ofAD.Aβ,especially in its oligomeric form,plays important roles in AD,causing cell death,calcium influx,loss of spines and repression of long-term potentiation (LTP)[1].However,recent studies indicate that in addition to Aβ,other fragments of APP after its cleavage,such as AICD,play essential roles in AD as well.In this article,the function of AICD and its underlying mechanisms will be reviewed.     

MicroRNA-98 induces an Alzheimer’s disease-like disturbance by targeting insulin-like growth factor 1

Alzheimer ’s disease（ A D） is a progressive neurodegenerative disorder characterized by extracellular senile plaques and intracellular neurofibrillary tangles.Many microRNAs（miRs） participate in regulating amyloid β（Aβ） formation and the metabolism of tau protein in the process of AD,and some are up-regulated in AD patients or transgenic models of AD.However,the role of miR-98 in AD remains unclear.Here,we showed that the expression of miR-98 was negatively correlated with the insulin-like growth factor 1（IGF-1） protein level in APP/PS1 mice.MiR-98 target sites in IGF-1 were confirmed by luciferase assay in HEK293 cells.Overexpression of miR-98 in N2a/APP cells down-regulated the IGF-1 protein level and promoted Aβ production,whereas inhibition of miR-98 in N2a/APP cells up-regulated the IGF-1 protein level and suppressed Aβ production.Furthermore,overexpression of miR-98 in N2a/WT cells increased the phosphorylation of tau,whereas inhibition of miR-98 reduced it.These results suggest that miR-98 increases Aβ formation and tau phosphorylation by inhibiting the translation of IGF-1,which might provide a therapeutic strategy for AD.     

MicroRNAs as diagnostic and therapeutic tools for Alzheimer's disease: advances and limitations

Alzheimer's disease(AD) is the most common age-related, progressive neurodegenerative disease. It is characterized by memory loss and cognitive decline and responsible for most cases of dementia in the elderly. Late-onset or sporadic AD accounts for 95% of cases, with age at onset 65 years. Currently there are no drugs or other therapeutic agents available to prevent or delay the progression of AD. The cellular and molecular changes occurring in the brains of individuals with AD include accumulation of β-amyloid peptide and hyperphosphorylated tau protein, decrease of acetylcholine neurotransmitter, inflammation, and oxidative stress. Aggregation of β-amyloid peptide in extracellular plaques and the hyperphosphorylated tau protein in intracellular neurofibrillary tangles are characteristic of AD. A major challenge is identifying molecular biomarkers of the early-stage AD in patients as most studies have been performed with blood or brain tissue samples(postmortem) at late-stage AD. Subjects with mild cognitive impairment almost always have the neuropathologic features of AD with about 50% of mild cognitive impairment patients progressing to AD. They could provide important information about AD pathomechanism and potentially also highlight minimally or noninvasive, easy-to-access biomarkers. MicroRNAs are dysregulated in AD, and may facilitate the early detection of the disease and potentially the continual monitoring of disease progression and allow therapeutic interventions to be evaluated. Four recent reviews have been published of microRNAs in AD, each of which identified areas of weakness or limitations in the reported studies. Importantly, studies in the last three years have shown considerable progress in overcoming some of these limitations and identifying specific microRNAs as biomarkers for AD and mild cognitive impairment. Further large-scale human studies are warranted with less disparity in the study populations, and using an appropriate method to validate the findings.     

ApoE2 and Alzheimer’s disease：time to take a closer look

正Alzheimer’s disease(AD)is the most common form of dementia among the elderly.It currently affects approximately 5.1 million Americans,a number predicted to triple by 2050.AD is clinically manifested as progressive loss of memory and cognitive function,and is characterized pathologically by the formation of amyloid-beta(Aβ)plaques and neurofibrillary tangles(NFT).Since its discovery in 1906,extensive     

GluN2B-NMDA receptors in Alzheimer’s disease：beyond synapse loss and cell death

<正>Alzheimer’s disease(AD) is one of the most devastating diseases affecting the life and health of aging population.Two hallmarks of AD are senile plaques and neurofibrillary tangles,and AD is well known for the massive loss of neurons and impaired cognitive functions especially memory loss.Despite extensive search for effective treatment,available     

Toxic tau: structural origins of tau aggregation in Alzheimer's disease

Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles.Most of the Alzheimer’s drugs targeting amyloidβhave been failed in clinical trials.Particularly,tau pathology connects greatly in the pathogenesis of Alzheimer’s disease.Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron.Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved.The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state.Therefore,aberrant phosphorylation,as well as truncation of tau protein,has come into focus as significant mechanisms that make tau protein in a pathological entity.Furthermore,the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely.In this review,we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease.     

How mind-body therapies might reduce pathological features of Alzheimer’s disease

Alzheimer’s disease(AD)is an irreversible neurodegenerat i ve disorder that i s responsible for around 60-80%of all dementia cases and currently affects around 50 million people worldwide.As the population’s life span tends to increase,current predictions suggest that by 2050,152 million people worldwide will suffer from dementia(Balsinha,2019).While the exact cause of AD remains obscure,various hypotheses regarding AD etiology have been described in the last decades.According to the amyloid hypothesis,the pathogenic changes related to AD start with the accumulation of amyloid-beta(Aβ)in the brain.These Aβpeptides form oligomers and insoluble amyloid plaques which are neurotoxic and trigger harmful downstream events such as the aggregation of the microtubule-associated protein Tau into neurofibrillary tangles,chronic inflammation,and brain atrophy.     

Pathogenic contribution of cholesteryl ester accumulation in the brain to neurodegenerative disorders

<正>Cholesteryl esters(CEs) have been increasingly implicated in neurodegenerative disorders such as Alzheimer’s disease(AD).Alois Alzheimer noted three prominent neuropathologic features in his original analysis of the AD brain:senile plaques,neurofibrillary tangles,and lipid granule accumulation.Senile plaques,which are aggregates of amyloid-beta(Aβ),and neurofibrillary tangles,which are aggregates of phosphorylated tau,have been regarded as more consistent characteristics of the AD brain...     

Calcium channel blockers and Alzheimer’s disease

Alzheimer’s disease is characterized by two pathological hallmarks: amyloid plaques and neurofi-brillary tangles. In addition, calcium homeostasis is disrupted in the course of human aging. Recent research shows that dense plaques can cause functional alteration of calcium signals in mice with Alzheimer’s disease. Calcium channel blockers are effective therapeutics for treating Alzheimer’s disease. This review provides an overview of the current research of calcium channel blockers in-volved in Alzheimer’s disease therapy.     

Microtubule affinity regulating kinase(MARK/Par1) isoforms differentially regulate Alzheimer-like TAU missorting and Aβ-mediated synapse pathology

<正>Importance of TAU protein for dementia syndromes:Dementia currently affects about 55 million people worldwide,with Alzheimer’s disease (AD) being the most prevalent form.The one crucial pathological hallmark of AD that correlates best with loss of synapses and cognitive decline are the so-called intracellular neurofibrillary tangles composed of mislocalized/missorted and hyperphosphorylated TAU protein (Naseri et al.,2019).Many other neurodegenerative diseases,both genetic and nongeneti...     

Pathological mechanisms and therapeutic strategies for Alzheimer's disease

Alzheimer's disease is a rather complex neurodegenerative disease,which is attributed to a combination of multiple factors.Among the many pathological pathways,synaptic dysfunctions,such as synapses loss and deficits in synaptic plasticity,were thought to be strongly associated with cognitive decline.The deficiencies in various sorts of neurotransmissions are responsible for the multifarious neurodegenerative symptoms in Alzheimer's disease,for example,the cholinergic and glutamatergic deficits for cognitive decline,the excitatory and inhibitory neurotransmission dyshomeostasis for synaptic plasticity deficits and epileptiform symptoms,and the monoamine neurotransmission for neuropsychiatric symptoms.Amyloid cascade hypothesis is the most popular pathological theory to explain Alzheimer's disease pathogenesis and attracts considerable attention.Multiple lines of genetic and pathological evidence support the predominant role of amyloid beta in Alzheimer's disease pathology.Neurofibrillary tangles assembled by microtubule-associated protein tau are other important histopathological characteristics in Alzheimer's disease brains.Cascade of tau toxicity was proved to lead to neuron damage,neuroinflammation and oxidative stress in brain.Ageing is the main risk factor of neurodegenerative diseases,and is associated with inflammation,oxidative stress,reduced metabolism,endocrine insufficiencies and organ failures.These aging related risk factors were also proved to be some of the risk factors contributing to Alzheimer's disease.In Alzheimer's disease drug development,many good therapeutic strategies have been investigated in clinical evaluations.However,complex mechanism of Alzheimer's disease and the interplay among different pathological factors call for the come out of allpowerful therapies with multiple curing functions.This review seeks to summarize some of the representative treatments targeting different pathological pathways currently under clinical evaluations.Multi-target therapies as an emerging strategy for Alzheimer's disease treatment will be highlighted.     

Tau Modulates Neurovascular Coupling

The microtubule-associated protein tau was identified in the neurofibrillary tangles(NFTs)of Alzheimer's disease(AD)more than 30 years ago,and its mutation can directly cause neurodegeneration.As implied by its purification from microtubules,tau was thought to stabilize microtubules and therefore to be of crucial importance in the brain.However,the physiological function of tau is still in debate since there is no detectable deficit in tau-knockout mice until they are 12 months old[1].Recently.     

Impairment of the nerve growth factor pathway driving amyloid accumulation in cholinergic neurons the incipit of the Alzheimer's disease story?

The current idea behind brain pathology is that disease is initiated by mild disturbances of common physiological processes. Overtime, the disruption of the neuronal homeostasis will determine irreversible degeneration and neuronal apoptosis. hTis could be also true in the case of nerve growth factor (NGF) al-terations in sporadic Alzheimer’s disease (AD), an age-related pathology characterized by cholinergic loss, amyloid plaques and neurofibrillary tangles. In fact, the pathway activated by NGF, a key neurotrophin for the metabolism of basal forebrain cholinergic neurons (BFCN), is one of the ifrst homeostatic systems affected in prodromal AD. NGF signaling dysfunctions have been thought for decades to occur in AD late stages, as a mere consequence of amyloid-driven disruption of the retrograde axonal transport of neuro-trophins to BFCN. Nowadays, a wealth of knowledge is potentially opening a new scenario: NGF signaling impairment occurs at the onset of AD and correlates better than amyloid load with cognitive decline. hTe recent acceleration in the characterization of anatomical, functional and molecular proifles of early AD is aimed at maximizing the efficacy of existing treatments and setting novel therapies. Accordingly, the elucidation of the molecular events underlying APP metabolism regulation by the NGF pathway in the sep-to-hippocampal system is crucial for the identiifcation of new target molecules to slow and eventually halt mild cognitive impairment (MCI) and its progression toward AD.