C/EBPβ/AEP Signaling Drives Alzheimer's Disease Pathogenesis

Alzheimer’s disease(AD)is the most common type of dementia.Almost two-thirds of patients with AD are female.The reason for the higher susceptibility to AD onset in women is unclear.However,hormone changes during the menopausal transition are known to be associated with AD.Most recently,we reported that follicle-stimulating hormone(FSH)promotes AD pathology and enhances cognitive dysfunctions via activating the CCAAT-enhancer-binding protein(C/EBPβ)/asparagine endopeptidase(AEP)pathway.This review summarizes our current understanding of the crucial role of the C/EBPβ/AEP pathway in driving AD pathogenesis by cleaving multiple critical AD players,including APP and Tau,explaining the roles and the mechanisms of FSH in increasing the susceptibility to AD in postmenopausal females.The FSH-C/EBPβ/AEP pathway may serve as a novel therapeutic target for the treatment of AD.

Preserving cognitive function in patients with Alzheimer's disease:The Alzheimer's disease neuroprotection research initiative(ADNRI)

The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.

Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer’s disease

Alzheimer’s disease(AD)is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques,hyperphosphorylated tau protein,and neurofibrillary tangles in the brain.The overexpression of amyloid-βprecursor protein(APP)in an AD brain results in the binding of APP intracellular domain(AICD)to Fe65 protein via the C-terminal Fe65-PTB2 interaction,which then triggers the secretion of amyloid-βand the consequent pathogenesis of AD.Apparently,targeting the interaction between APP and Fe65 can offer a promising therapeutic approach for AD.Recently,exosome,a type of extracellular vesicle with diameter around 30–200 nm,has gained much attention as a potential delivery tool for brain diseases,including AD,due to their ability to cross the blood–brain barrier,their efficient uptake by autologous cells,and their ability to be surface-modified with target-specific receptor ligands.Here,the engineering of hippocampus neuron cell-derived exosomes to overexpress Fe65,enabled the development of a novel exosome-based targeted drug delivery system,which carried Corynoxine-B(Cory-B,an autophagy inducer)to the APP overexpressed-neuron cells in the brain of AD mice.The Fe65-engineered HT22 hippocampus neuron cell-derived exosomes(Fe65-EXO)loaded with Cory-B(Fe65-EXO-Cory-B)hijacked the signaling and blocked the natural interaction between Fe65 and APP,enabling APP-targeted delivery of Cory-B.Notably,Fe65-EXO-Cory-B induced autophagy in APP-expressing neuronal cells,leading to amelioration of the cognitive decline and pathogenesis in AD mice,demonstrating the potential of Fe65-EXO-Cory-B as an effective therapeutic intervention for AD.

Netrin-1 signaling pathway mechanisms in neurodegenerative diseases

Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development.Their profound impacts then extend into adulthood to encompass the maintenance of neuronal survival and synaptic function.Increasing amounts of evidence highlight several key points:(1)Diminished Netrin-1 levels exacerbate pathological progression in animal models of Alzheimer’s disease and Parkinson’s disease,and potentially,similar alterations occur in humans.(2)Genetic mutations of Netrin-1 receptors increase an individuals’susceptibility to neurodegenerative disorders.(3)Therapeutic approaches targeting Netrin-1 and its receptors offer the benefits of enhancing memory and motor function.(4)Netrin-1 and its receptors show genetic and epigenetic alterations in a variety of cancers.These findings provide compelling evidence that Netrin-1 and its receptors are crucial targets in neurodegenerative diseases.Through a comprehensive review of Netrin-1 signaling pathways,our objective is to uncover potential therapeutic avenues for neurodegenerative disorders.

7,8-dihydroxyflavone,a small molecular TrkB agonist,is useful for treating various BDNF-implicated human disorders

Brain-derived neurotrophic factor(BDNF)regulates a variety of biological processes predominantly via binding to the transmembrane receptor tyrosine kinase TrkB.It is a potential therapeutic target in numerous neurological,mental and metabolic disorders.However,the lack of efficient means to deliver BDNF into the body imposes an insurmountable hurdle to its clinical application.To address this challenge,we initiated a cell-based drug screening to search for small molecules that act as the TrkB agonist.7,8-Dihydroxyflavone(7,8-DHF)is our first reported small molecular TrkB agonist,which has now been extensively validated in various biochemical and cellular systems.Though binding to the extracellular domain of TrkB,7,8-DHF triggers TrkB dimerization to induce the downstream signaling.Notably,7,8-DHF is orally bioactive that can penetrate the brain blood barrier(BBB)to exert its neurotrophic activities in the central nervous system.Numerous reports suggest 7,8-DHF processes promising therapeutic efficacy in various animal disease models that are related to deficient BDNF signaling.In this review,we summarize our current knowledge on the binding activity and specificity,structure-activity relationship,pharmacokinetic and metabolism,and the pre-clinical efficacy of 7,8-DHF against some human diseases.

δ-secretase in neurodegenerative diseases: mechanisms, regulators and therapeutic opportunities

Mammalian asparagine endopeptidase(AEP)is a cysteine protease that cleaves its protein substrates on the Cterminal side of asparagine residues.Converging lines of evidence indicate that AEP may be involved in the pathogenesis of several neurological diseases,including Alzheimer’s disease,Parkinson’s disease,and frontotemporal dementia.AEP is activated in the aging brain,cleaves amyloid precursor protein(APP)and promotes the production of amyloid-β(Aβ).We renamed AEP to δ-secretase to emphasize its role in APP fragmentation and Aβ production.AEP also cleaves other substrates,such as tau,α-synuclein,SET,and TAR DNA-binding protein 43,generating neurotoxic fragments and disturbing their physiological functions.The activity of δ-secretase is tightly regulated at both the transcriptional and posttranslational levels.Here,we review the recent advances in the role of δ-secretase in neurodegenerative diseases,with a focus on its biochemical properties and the transcriptional and posttranslational regulation of its activity,and discuss the clinical implications of δ-secretase as a diagnostic biomarker and therapeutic target for neurodegenerative diseases.

Unbiased transcriptomic analyses reveal distinet effects of immune deficiency in CNS function with and without injury

The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.