Autophagy and Alzheimer's Disease: Mechanisms and Impact Beyond the Brain

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by neuronal loss, cognitive decline, and pathological hallmarks such as amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. Recent evidence highlights autophagy as a pivotal mechanism in cellular homeostasis, mediating the clearance of misfolded proteins and damaged organelles. However, impaired autophagy contributes significantly to AD pathogenesis by disrupting proteostasis, exacerbating neuroinflammation, and promoting synaptic dysfunction. This review aims to scrutinize the intricate relationship between autophagy dysfunction and AD progression, explaining key pathways including macroautophagy, chaperone-mediated autophagy (CMA), and selective autophagy processes such as mitophagy and aggrephagy. This further extends the discussion beyond the central nervous system, evaluating the role of hepatic autophagy in Aβ clearance and systemic metabolic regulation. An understanding of autophagy's involvement in AD pathology via various mechanisms could give rise to a novel therapeutic strategy targeting autophagic modulation to mitigate disease progression in the future.

Keywords: Alzheimer’s disease; amyloid-beta clearance; autophagy; neurodegeneration; tau pathology.

Figure 1

Schematic illustration of the five major stages of macroautophagy: (1) initiation begins with activation of the Unc-51-like autophagy-activating kinase (ULK) complex (ULK1/2, ATG13, ATG101, and FAK family kinase-interacting protein of 200 kDa or FIP200), triggering downstream events; (2) nucleation involves the vacuolar protein sorting 34 (VPS34) complex (including VPS34, VPS15, Beclin-1, and Atg14L) generating phosphatidylinositol 3-phosphate (PtdIns3P) at the phagophore formation site near the endoplasmic reticulum; (3) elongation is mediated by the conjugation systems involving Atg9p, Atg8p/LC3I/LC3II, Atg12–Atg5–Atg16L complex, expanding the phagophore membrane; (4) closure leads to the formation of a double-membraned autophagosome, facilitated by soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) proteins and RAB GTPases; and (5) fusion merges the autophagosome with a lysosome to form an autolysosome, enabling degradation of the enclosed cytoplasmic material. This pathway is essential for cellular homeostasis and the clearance of damaged organelles and proteins.

Figure 2

Schematic illustration of selective autophagy pathways and their implications in human diseases. Selective autophagy is activated under nutrient-deprived conditions through the inhibition of mechanistic target of rapamycin complex 1 (mTORC1) and activation of ULK1 kinase, leading to targeted degradation of specific organelles or protein aggregates. Various forms include the following: Mitophagy (mitochondrial clearance), regulated by PTEN-induced kinase 1/parkin (PINK1/Parkin), associated with neurodegeneration in autophagy-deficient states. Lysophagy (lysosomal turnover), critical in infections and cancer, is mediated by ubiquitination and autophagy receptors such as Tax1 (Human T-cell Leukemia Virus Type I) binding protein 1 (or TAX1BP1) and p62. Pexophagy (peroxisome degradation), involving peroxisomal biogenesis factor 3 (PEX3) and NRB1, affects metabolic disorders. Aggrephagy (clearance of protein aggregates), relevant to Alzheimer’s disease pathology, employing TAX1BP1, NRB1, and p62. ER-phagy (endoplasmic reticulum turnover), regulated by receptors like family with sequence similarity 134 member B (FAM134B) and cell cycle progression gene 1 (CCPG1), is implicated in peripheral neuropathy. Each process recruits LC3-interacting autophagy adaptors to facilitate engulfment by the autophagosome. Dysfunction in these selective autophagy pathways contributes to various human diseases.

Figure 3

Schematic illustration of the steps involved in chaperone-mediated autophagy (CMA). Substrate proteins containing a KFERQ-like motif are recognized by the cytosolic chaperone heat shock cognate 71-kDa protein (HSC70), forming a substrate–HSC70 complex. This complex is then targeted to the lysosomal membrane, where it binds to the lysosome-associated membrane protein type 2A (LAMP-2A). Upon binding, LAMP-2A undergoes multimerization to form a translocation complex, facilitating the unfolding and transport of the substrate protein into the lysosomal lumen for degradation.

Figure 4

Presenilin 2 (PS2)-mediated amyloid beta (Aβ) synthesis in the liver and its contribution to cerebral amyloid burden. PS2 activity in the liver promotes the synthesis of Aβ, which can enter the brain via the blood–brain barrier (BBB) through the receptor for advanced glycation end-products (RAGE), contributing to cerebral Aβ accumulation. Clearance of Aβ from the brain occurs via the glymphatic system, the brain’s waste removal pathway. Intracellularly, misfolded protein aggregates, including Aβ, are targeted for degradation by autophagy. The cargo adaptor proteins p62 (also known as Sequestosome 1 or SQSTM1) and NBR1 bind ubiquitinated protein aggregates and facilitate their delivery to autophagosomal membrane proteins such as microtubule-associated protein 1A/1B light chain 3 (LC3), enabling lysosomal degradation and maintaining proteostasis.