Autophagy in alzheimer’s disease: A cleaning service out-of-order?

Abstract

Autophagy is a major route for the degradation of protein aggregates and damaged organelles. Alzheimer’s disease (AD) is mainly characterized by two distinctive neuropathological lesions, the accumulation of amyloid-ß (Aß) deposits and the presence of neurofibrillary tangles composed of hyperphosphorylated tau protein, which clearly indicates that the mechanisms of neuronal housekeeping and protein quality control are compromised in AD pathology. Indeed, the AD brain is marked by defects in the retrograde transport of autophagosomes and their maturation to lysosomes, which trigger a massive accumulation of autophagic vacuoles within large swellings along dystrophic and degenerating neurites. The combination of altered induction of the autophagic process and hampered lysosomal clearance of autophagic substrates creates conditions favorable for Aß and tau accumulation in AD. Understanding the step(s) affected during the autophagic process in the different stages of AD is essential for the development of novel therapeutic approaches. In this chapter, the current knowledge pertaining to the cellular and molecular mechanisms involved in autophagy and its important role in the progression of AD pathology will be highlighted. The ongoing drug discovery strategies for therapeutic modulation of autophagy in the context of AD will also be discussed.