Toxicity and Autophagy in Neurodegenerative Disorders by José M. Fuentes

Author:José M. Fuentes
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

Final Remarks

Substantial progress has been made in the past few years in understanding the mechanisms underlying defective autophagy in AD pathology. Autophagic vacuoles accumulated in dystrophic neurites are major sites of Aβ generation, where autophagy regulates AβPP turnover and stimulates γ-secreatase activity and Aβ clearance. Abnormal processing and altered clearance by autophagic-lysosomal machinery of tau protein is also implicated AD pathology. Recent breakthroughs also revealed that dysfunctional mitochondria are tagged for degradation by autophagy (mitophagy) in an attempt to maintain an healthy mitochondrial pool. In line with this, therapeutic modulation of autophagy has been shown to mitigate Aβ and tau pathologies and cognitive deficits in experimental models of AD. However, during the implementation of this therapeutics , the nature of the autophagic defect, the timing of intervention, and the optimal level and duration of autophagy stimulation should be considered. Although up-regulation of autophagy might be beneficial during the early stages of AD, increasing autophagic input may backfire if applied to later stages of AD, in which the lysosomal blockage is preeminent.

A better understanding of the precise role of autophagy in the different stages of AD progression will show promise as an avenue for future therapy against this incurable disease.

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