Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications

Abstract

Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid β (Aβ), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aβ is dysregulated, which leads to the accumulation and aggregation of Aβ. Metabolism of Aβ and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.

Keywords: Alzheimer’s disease; amyloid beta; autophagy; tau.

FIGURE 1

Representation of proteins and protein complexes involved in the “Autophagy – animal” KEGG pathway. This figure was taken from the KEGG database (http://www.genome.jp/kegg-bin/show_pathway?ko04140) and modified. Blue boxes mark the proteins that are associated with AD. Orange boxes mark additional proteins that are not originally included in the pathway. These genes are associated with both AD and autophagy, and are discussed in the present review. Red, blue, and violet lines mark partners with which the additional proteins interact (red color means activation, blue color means inhibition, and violet color means unspecified or complex (e.g., both inhibitory and stimulatory effect) according to STRING database). The interactions data were extracted from the STRING database (http://string-db.org). To assure that the presented data is reliable, we have included only interactions that showed at least medium STRING confidence score and were either identified in an experiment or are annotated in manually curated databases. Additionally, we have added interaction between GFAP and LAMP, which was not included in STRING database but was found by manual literature search. Permission to use KEGG figure was granted.

FIGURE 2

Connections between genes discussed in the “Genes Common to Autophagy and AD” section and (A) neuroinflammation as well as (B) cannabinoids. This figure was drawn based on data obtained using the Chilibot tool. Black arrows mark relationships that are neither obviously stimulatory nor inhibitory. Orange arrow marks both stimulatory and inhibitory relationship. Red arrow marks inhibitory relationship. Green arrow mark stimulatory relationship. The respective numbers mark the weight of the relationship according to the Chilibot tool.