Abstract
Alzheimer’s disease (AD) is characterized by the formation of intracellular aggregate composed of heavily phosphorylated tau protein and extracellular deposit of amyloid-β (Aβ) plaques derived from proteolysis cleavage of amyloid precursor protein (APP). Autophagy refers to the lysosomal-mediated degradation of cytoplasmic constituents, which plays a critical role in maintaining cellular homeostasis. Importantly, recent studies reported that dysregulation of autophagy is associated in the pathogenesis of AD, and therefore, autophagy modulation has gained attention as a promising approach to treat AD pathogenesis. In AD, both the maturation of autolysosomes and its retrograde transports have been obstructed, which causes the accumulation of autophagic vacuoles and eventually leads to degenerating and dystrophic neurites function. However, the mechanism of autophagy modulation in APP processing and its pathogenesis have not yet been fully elucidated in AD. In the early stage of AD, APP processing and Aβ accumulation-mediated autophagy facilitate the removal of toxic protein aggregates via mTOR-dependent and -independent pathways. In addition, a number of autophagy-related genes (Atg) and APP are thought to influence the development of AD, providing a bidirectional link between autophagy and AD pathology. In this review, we summarized the current observations related to autophagy regulation and APP processing in AD, focusing on their modulation associated with the AD progression. Moreover, we emphasizes the application of small molecules and natural compounds to modulate autophagy for the removal and clearance of APP and Aβ deposits in the pathological condition of AD.
Highlights
Alzheimer’s disease (AD) is the most irreversible and progressive brain disorder of neurodegenerative disease characterized by the accumulation of extracellular amyloid beta (Aβ) leading to the formation of senile plaques and intracellular tau aggregates that form neurofibrillary tangles (NFTs) in the brain [1,2]
Growing evidence suggests that soluble APPα plays a neuroprotective role and functions similar to growth factors, and it has been shown that the Amyloid precursor protein (APP) intracellular domain (AICD) interacts with numerous proteins involved theasregulation of transcription and axonal transport [48]
C99 fragThe amyloidogenic processing of APP, which is first mediated byand β-secretase, leads to ments are cleaved by γ-secretase, which produces two fragments known as Aβ carthe production of afragment large soluble amyloid precursor domain protein(AICD)
Summary
Alzheimer’s disease (AD) is the most irreversible and progressive brain disorder of neurodegenerative disease characterized by the accumulation of extracellular amyloid beta (Aβ) leading to the formation of senile plaques and intracellular tau aggregates that form neurofibrillary tangles (NFTs) in the brain [1,2]. A self-digesting mechanism, is an intracellular cleansing process characterized by the engulfment of malformed proteins and damaged cellular organelles by membrane-bound vesicles known as autophagosomes [17]. These autophagosomes subsequently fuse with the lysosomes to form autolysosomes resulting degradation of dysfunctional materials by lysosomal acid hydrolases [19]. Progression of AD deregulates the autophagy pathway, resulting in the continuous generation of Aβ, which exaggerates both autophagy malin the continuous generation of Aβ, which exaggerates both autophagy malfunction and function and AD [21] Both oligonucleotides and proteins, such as miRNAs, AD [21]. Targeting autophagy may have a profound role in AD management [23]
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