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

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.

Suppression of mature TAU isoforms prevents Alzheimer's disease-like amyloid-beta oligomer-induced spine loss in rodent neurons

Introduction:TAU isoforms as disease mediators:The microtubule-associated protein TAU is predominantly present in the axons of neurons under physiological conditions.In Alzheimer’s disease(AD)and related tauopathies,TAU also mislocalizes("TAU missorting")to the soma and the dendrites,where it eventually forms aggregates,the so-called neurofibrillary tangles(for review see Zimmer-Bensch and Zempel,2021;Zempel,2023).

Targeting tau in Alzheimer's disease:from mechanisms to clinical therapy

Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.

Genetic and epigenetic targets of natural dietary compounds as anti-Alzheimer's agents

Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults.Pathogenic factors,such as oxidative stress,an increase in acetylcholinesterase activity,mitochondrial dysfunction,genotoxicity,and neuroinflammation are present in this syndrome,which leads to neurodegeneration.Neurodegenerative pathologies such as Alzheimer’s disease are considered late-onset diseases caused by the complex combination of genetic,epigenetic,and environmental factors.There are two main types of Alzheimer’s disease,known as familial Alzheimer’s disease(onset<65 years)and late-onset or sporadic Alzheimer’s disease(onset≥65 years).Patients with familial Alzheimer’s disease inherit the disease due to rare mutations on the amyloid precursor protein(APP),presenilin 1 and 2(PSEN1 and PSEN2)genes in an autosomaldominantly fashion with closely 100%penetrance.In contrast,a different picture seems to emerge for sporadic Alzheimer’s disease,which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology.Importantly,the fundamental pathophysiological mechanisms driving Alzheimer’s disease are interfaced with epigenetic dysregulation.However,the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer’s disease or following injury or stroke in humans.In recent years,there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer’s disease.Through epigenetic mechanisms,such as DNA methylation,non-coding RNAs,histone modification,and chromatin conformation regulation,natural compounds appear to exert neuroprotective effects.While we do not purport to cover every in this work,we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer’s disease-related genes.

Sorl1 knockout inhibits expression of brain-derived neurotrophic factor:involvement in the development of late-onset Alzheimer's disease

Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.

Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease

Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer’s disease.Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases,including Parkinson’s and Huntington’s diseases,however,the effect of Citri Reticulatae Semen on Alzheimer’s disease remains unelucidated.In the current study,the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated.Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy.In addition,Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro,and suppress amyloid-beta-induced pathology such as paralysis,in a transgenic Caenorhabditis elegans in vivo model.Moreover,genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent.Most importantly,Citri Reticulatae Semen extract was confirmed to improve cognitive impairment,neuronal injury and amyloid-beta burden in 3×Tg Alzheimer’s disease mice.As revealed by both in vitro and in vivo models,these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer’s disease via its neuroprotective autophagic effects.

Ferroptosis mechanism and Alzheimer's disease

Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms.Ferroptosis is a classic regulatory mode of cell death.Extensive studies of regulatory cell death in Alzheimer’s disease have yielded increasing evidence that fe rroptosis is closely related to the occurrence,development,and prognosis of Alzheimer’s disease.This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferro ptosis in Alzheimer’s disease.Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer’s disease.

Neural stem cell-derived exosomes promote mitochondrial biogenesis and restore abnormal protein distribution in a mouse model of Alzheimer's disease

Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheimer’s disease affects the entire brain,further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole.Here,we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing,immunostaining,and lightsheet imaging to clarify their spatial distribution.Additionally,to clarify whether the sirtuin 1(SIRT1)-related pathway plays a regulatory role in neural stem cell-de rived exosomes interfering with mitochondrial functional changes,we generated a novel nervous system-SIRT1 conditional knoc kout AP P/PS1mouse model.Our findings demonstrate that neural stem cell-de rived exosomes significantly increase SIRT1 levels,enhance the production of mitochondrial biogenesis-related fa ctors,and inhibit astrocyte activation,but do not suppress amyloid-βproduction.Thus,neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer’s disease that activates the SIRT1-PGC1αsignaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis.In addition,we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in Alzheimer’s disease,and that neural stem cell-derived exosome treatment can reverse this effect,indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.

Detection and clearance in Alzheimer’s disease: leading with illusive chemical, structural and morphological features of the targets

Highly specific interactions between biomolecules,such as antigen-antibody,protein-ligand,or nucleic acid base pair complementary are on the basis of the organization of complex organisms.The same principles may be tentatively used in molecular medicine for diagnosis and therapeutics.A molecule can be designed to selectively bind a protease and thereby inhibit the production of a peptide that forms toxic aggregates in the brain or an antibody may be produced to bind specifically to that peptide for detection or clearance purposes.Unfortunately,interference in biological systems is not that simple.For a start there is the inhibition of the physiological role of the protease;moreover,several cleavage fragments may be produced,which may continue to diverge due to putative post-translational modification and self-assembly processes,hiding the toxic target in a“soup”of peptide species varying in size,structure and chemical composition.A perspective of the current status and challenges in targeting peptide species for diagnosis and treatment in the context of Alzheimer’s disease is given.

Small molecular decoys in Alzheimer's disease

Recent progress in the treatment of Alzheimer’s disease(AD)using antibodies against amyloid sustains amyloid generation as a key process in AD.Amyloid formation starts with two amyloidbeta(Aβ)molecules interacting(dimer formation)followed by an accelerating build-up of socalled protofibrils,which turn into fibrils,which accumulate in the characteristic plaques.

Probing the endoplasmic reticulummitochondria interaction in Alzheimer's disease:searching far and wide

Alzheimer's disease(AD)is the most frequent,form of dementia in elderly people and is an incurable disease with an exponentially growing number of cases.Extracellular deposition of amyloid-β(Aβ)plaques and intraneuronal formation of neurofibrillary tangles represent neuropathological hallmarks of AD.

Autolysosomal acidification impairment as a mediator for TNFR1 induced neuronal necroptosis in Alzheimer’s disease

Neuronal necroptosis-an emerging form of regulated cell death associated with neuroinflammatory signaling:Alzheimer’s disease(AD)is characterized by the presence of extracellular amyloid-β(Aβ)plaques and intracellular tau neurofibrillary tangles as well as progressive neuronal loss.Recent evidence has suggested that prolonged neuroinflammation with increased levels of cytokines,arising from neuronal injury,innate immune responses from glial cells,and peripheral inflammation,leads to neuronal death and AD progression.

Potential of molecular chaperones for treating Alzheimer’s disease

Alzheimer’s disease(AD)is the most prevalent form of dementia,i.e.,progressive memory loss and profound cognitive dysfunction,resulting in a considerable societal burden.At the neuropathological level,the brains of AD patients exhibit amyloid-β(Aβ)plaques,neurofibrillary tangles,and neuroinflammation(Sala Frigerio and De Strooper,2016).

Are we close to using Alzheimer blood biomarkers in clinical practice?

Alzheimer's disease(AD) is a progressive neurodegenerative disease histologically characterized by the presence of extraneuronal plaques,mainly formed by the 42-aminoacid isoform of amyloid-(Aβ_(1-42)),and by intraneuronal neurofibrillary to ngles,mainly formed by the tau protein and its hyperphosphorylated isoforms(p-tau).AD is the most common cause of dementia,with an estimated lifetime risk of about 1 in 10 for men and 1 in 5 for women.

A seed and soil model of loneliness in Alzheimer's disease

Loneliness is classically defined as a result of perceiving a discrepancy between the desired quantity and quality of one's social life and actual social relationships(Perlman and Peplau,1984).Lifespan research has indicated older adults are among the highest risk for experiencing loneliness because their social network size decreases more frequently than that of younger adults.

Targeting calcium signaling in Alzheimer’s disease: challenges and promising therapeutic avenues

The critical role of calcium dyshomeostasis in the pathogenesis of Alzheimer’s disease(AD):AD is a progressive neurodegenerative disease characterized by cognitive decline,memory impairment,and behavioral changes.With an estimated 50 million people being affected worldwide,the incidence of AD is constantly increasing globally.The hallmark of AD is the accumulation of amyloid-beta protein(Aβ)in the form of amyloid plaques and hyperphosphorylated tau protein in the form of neurofibrillary tangles.However,increasing evidence suggests that calcium ion(Ca2+)dysregulation also plays a crucial role in the pathogenesis of AD(Calvo-Rodriguez and Bacskai,2021).As a key second messenger,Ca2+regulates a wide range of cellular processes,including the release of neurotransmitters,gene expression,and cell death.Ca^(2+)also regulates the activity of Calcium/calmodulin-dependent protein kinase II,which is critical for synaptic plasticity,learning,and memory(Kaushik et al.,2022).Alternation in the Ca^(2+)signal is an early event in the pathogenesis of AD,which can lead to synaptic dysfunction,neuronal loss,and cognitive impairment.

Medin synergized with vascular amyloid-beta deposits accelerates cognitive decline in Alzheimer's disease:a potential biomarker

Brain vascular dysfunction in Alzheimer s disease(AD) pathogenesis has become increasingly clea r.Accumulating evidence shows that damaged vascular,including large or small vessels and even neurovascular unit,may accelerate the neuropathological process of AD via disrupting brain hypoperfusion,aberrant angiogenesis,and neuroinflammatory response,etc.Thus,vascular dysfunction makes a substantially contribution to the cognitive decline of AD patients.

Recent advances and future therapy development for Alzheimer’s disease and related disorders

Over 55 million people globally live with Alzheimer’s disease(AD)or related dementias(ADRD)and the number is expected to double every twenty years.Unt i l recent l y,onl y symptomatic treatments were available to patients with AD,including acetylcholine esterase inhibitors,of which the last one,galantamine,was approved by the US Food and Drug Administration(FDA)in 2001.

Alterations of protein homeostasis in Alzheimer's disease:beyond Procrustean bed of endoplasmic reticulum stress and unfolded protein response

Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and society.Neuropathological hallmarks of AD,evident in postmortem AD brains,include a massive loss of the grey matter in the neocortex,extracellular deposition of amyloid-β(Aβ)in the form of senile plaques and cerebrovascular amyloid angiopathy,and intra-neuronal accumulation of neurofibrillary tangles,formed by hyper-phosphorylated tau protein.

Microglial autophagy in neurogenesis:a new player in Alzheimer's disease

While extensive studies have illuminated the impact of Alzheimer's disease(AD) on neuronal survival,there is growing evidence that abnormal postnatal neurogenesis in early AD brains contributes to disease progression.Postnatal neurogenesis serves as a mechanism to replace dead or damaged neurons.New neurons generated from neural stem cells(NSCs) in the subgranular zone(SGZ) of the dentate gyrus integrate into the existing hippocampal circuit.