Cell “Self‐Eating” (Autophagy) Mechanism in Alzheimer's Disease

Funderburk, Sarah F.; Marcellino, Bridget; Yue, Zhenyu

doi:10.1002/msj.20161

Cited by 119 publications

(83 citation statements)

References 83 publications

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“…Microtubule-based long-distance axonal transport is essential for autophagic clearance because autophagosomes are predominantly generated in distal axons and mainly rely on retrograde transport to somatic lysosomes for degradation (23,29,(31)(32)(33). Defective autophagy has been implicated in AD pathogenesis (27,42,43). The presence of massively accumulated AVs in dystrophic (swollen) neurites is a unique feature linked to AD pathology (38,44).…”

Section: Discussionmentioning

confidence: 99%

Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation

Feng¹,

Tammineni²,

Agrawal

et al. 2017

Journal of Biological Chemistry

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Edited by George N. DeMartino ␤-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal ␤-secretase for amyloid-␤ generation and is degraded in lysosomes. The autophagy-lysosomal system plays a key role in the maintenance of cellular homeostasis in neurons. Recent studies established that nascent autophagosomes in distal axons move predominantly in the retrograde direction toward the soma, where mature lysosomes are mainly located. However, it remains unknown whether autophagy plays a critical role in regulation of BACE1 trafficking and degradation. Here, we report that induction of neuronal autophagy enhances BACE1 turnover, which is suppressed by lysosomal inhibition. A significant portion of BACE1 is recruited to the autophagy pathway and co-migrates robustly with autophagic vacuoles along axons. Moreover, we reveal that autophagic vacuole-associated BACE1 is accumulated in the distal axon of Alzheimer's disease-related mutant human APP transgenic neurons and mouse brains. Inducing autophagy in mutant human APP neurons augments autophagic retention of BACE1 in distal axons, leading to enhanced ␤-cleavage of APP. This phenotype can be reversed by Snapin-enhanced retrograde transport, which facilitates BACE1 trafficking to lysosomes for degradation. Therefore, our study provides new insights into autophagy-mediated regulation of BACE1 turnover and APP processing, thus building a foundation for future development of potential Alzheimer's disease therapeutic strategies.Accumulation of senile plaques is a pathological hallmark of Alzheimer's disease (AD).3 Amyloid-␤ (A␤) peptide is the main constituent of senile plaques and is derived from a sequential proteolysis of amyloid precursor protein (APP) by ␤-and ␥-secretases. ␤-Secretase is the initial and rate-limiting enzyme of this process (1-4). ␤-Site APP-cleaving enzyme 1 (BACE1) is the major neuronal ␤-secretase for A␤ generation (1-4). BACE1 levels increase with age (5) and are elevated in AD patient brains (6), thereby making BACE1 a prime target for therapeutic intervention (7-9). BACE1 is synthesized in the endoplasmic reticulum and then delivered to the cell surface from the trans-Golgi network (TGN). Mature BACE1 traffics to endosomes via internalization from the plasma membrane or directly from the TGN (3, 10 -12). The endosomal compartments (especially late endosomes (LEs) or multivesicular bodies) provide an acidic environment that is crucial for optimal ␤-secretase activity (10, 13-17), whereas BACE1 is ultimately degraded within lysosomes (15, 18 -20). Given that mature lysosomes are mainly located in the soma of neurons (21-24), proper retrograde transport of LE-loaded BACE1 is critical for the trafficking of BACE1 to lysosomes for turnover (20).Autophagy is the major cellular degradation pathway for long-lived proteins and damaged organelles (25-28). Altered autophagy has been linked to several major age-related neurodegenerative diseases, including AD (27). Recent studies established that autophagosomes are continuously...

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Section: Discussionmentioning

confidence: 99%

Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation

Feng¹,

Tammineni²,

Agrawal

et al. 2017

Journal of Biological Chemistry

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“…Accumulation of neuroproteins can cause neurodegenerative diseases, such as Alzheimer disease (AD), Parkinson disease (PD), Huntington disease and stroke, which result from a reduced level of autophagy. [6][7][8][9][10][11] In the autophagy gene superfamily, autophagy-related gene 5 (atg5) is a key gene. ATG5 protein can conjugate to ATG12 and then form a complex with the multimeric protein ATG16.…”

Section: Introductionmentioning

confidence: 99%

Expression pattern and functions of autophagy-related geneatg5in zebrafish organogenesis

Zhang²,

Zhang³

2011

Autophagy

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The implications of autophagy-related genes in serious neural degenerative diseases have been well documented. However, the functions and regulation of the family genes in embryonic development remain to be rigorously studied. Here, we report on for the first time the important role of atg5 gene in zebrafish neurogenesis and organogenesis as evidenced by the spatiotemporal expression pattern and functional analysis. Using morpholino oligo knockdown and mRNA overexpression, we demonstrated that zebrafish atg5 is required for normal morphogenesis of brain regionalization and body plan as well as for expression regulation of neural gene markers: gli1, huC, nkx2.2, pink1, β-synuclein, xb51 and zic1. We further demonstrated that ATG5 protein is involved in autophagy by LC3-II/LC3I ratio and rapamycin-induction experiments, and that ATG5 is capable of regulating expression of itself gene in the manner of a feedback inhibition loop. In addition, we found that expression of another autophagy-related gene, atg12, is maintained at a higher constant level like a housekeeping gene. This indicates that the formation of the ATG12-ATG5 conjugate may be dependent on ATG5 protein generation and its splicing, rather than on ATG12 protein in zebrafish. Importantly, in the present study, we provide a mechanistic insight into the regulation and functional roles of atg5 in development of zebrafish nervous system.

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“…These microtubules provide support for structural changes, axonal transport, and neuronal growth [69,82,83] . In the CNS, the τ protein presents itself in 6 different isoforms that vary in the number of binding sites for microtubules and the amount of exons they possess [82] .…”

Section: The Tau (τ) Proteinmentioning

confidence: 99%

“…The endosomal lysosomal pathway is also an important regulator of the processing of APP [67,68] and of the tau protein metabolism [69] . Because of the importance of this pathway for cellular maintenance and its role in the immune system, recent studies suggest that dysfunctions in neuronal autophagy causing an increase in the amount and size of endosomes at the cellular level, may be involved in the pathogenesis of AD [70][71][72][73][74] , as these changes are seen before the appearance of senile plaques and neurofibrillary tangles in the brain [72,74] .…”

Section: The Amyloid Hypothesismentioning

confidence: 99%

Molecular Pathogenesis of Alzheimer's Disease: An Update

2017

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Dementia is a chronic or progressive syndrome, characterized by impaired cognitive capacity beyond what could be considered a consequence of normal aging. It affects the memory, thinking process, orientation, comprehension, calculation, learning ability, language, and judgment; although awareness is usually unaffected. Alzheimer's disease (AD) is the most common form of dementia; symptoms include memory loss, difficulty solving problems, disorientation in time and space, among others. The disease was first described in 1906 at a conference in Tubingen, Germany by Alois Alzheimer. One hundred and ten years since its first documentation, many aspects of the pathophysiology of AD have been discovered and understood, however gaps of knowledge continue to exist. This literature review summarizes the main underlying neurobiological mechanisms in AD, including the theory with emphasis on amyloid peptide, cholinergic hypothesis, glutamatergic neurotransmission, the role of tau protein, and the involvement of oxidative stress and calcium.

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Cell “Self‐Eating” (Autophagy) Mechanism in Alzheimer's Disease

Cited by 119 publications

References 83 publications

Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation

Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation

Expression pattern and functions of autophagy-related geneatg5in zebrafish organogenesis

Molecular Pathogenesis of Alzheimer's Disease: An Update

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