Lipid Metabolism Influence on Neurodegenerative Disease Progression: Is the Vehicle as Important as the Cargo?

Abstract

Many neurodegenerative diseases are characterized by abnormal protein aggregates, including the two most common neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD). In the global search to prevent and treat diseases, most research has been focused on the early stages of the diseases, including how these pathogenic protein aggregates are initially formed. We argue, however, that an equally important aspect of disease etiology is the characteristic spread of protein aggregates throughout the nervous system, a key process in disease progression. Growing evidence suggests that both alterations in lipid metabolism and dysregulation of extracellular vesicles (EVs) accelerate the spread of protein aggregation and progression of neurodegeneration, both in neurons and potentially in surrounding glia. We will review how these two pathways are intertwined and accelerate the progression of AD and PD. Understanding how lipid metabolism, EV biogenesis, and EV uptake regulate the spread of pathogenic protein aggregation could reveal novel therapeutic targets to slow or halt neurodegenerative disease progression.

Keywords: Alzheimer’s disease; Parkinson’s disease; ceramide; extracellular vesicle; glia; glucocerebrosidase (GBA); lipid metabolism; protein aggregation and propagation.

Figure 1

Exosome biogenesis is dysregulated by lysosomal GBA deficiencies. Extracellular proteins are endocytosed and trafficked intracellularly via endocytes, where they undergo multiple rounds of inward budding to generate intraluminal vesicles (ILVs) within late endosomes/multivesicular bodies (MVBs). MVBs can fuse with the lysosome for degradation or fuse with the plasma membrane, where ILVs are released as extracellular vesicles (EVs). We hypothesize that GBA deficiency impairs lysosomal degradation, leading to the accumulation of intracellular protein aggregates and increased trafficking of the MVB to the plasma membrane for EV biogenesis.

Figure 2

Endocytosis of synaptic vesicles (SVs) can occur through four pathways: (1) “kiss-and-run” endocytosis; (2) ultrafast endocytosis; (3) clathrin-mediated endocytosis; and (4) bulk endocytosis. In Alzheimer’s disease (AD), pathogenic tau can bind to the SVs which can lead them to be less mobile, inducing SV clustering and reducing neurotransmission.

Figure 3

Glial cells mediate propagation of neurodegenerative protein species by up-taking both free and extra-cellular vesicle (EV)-associated proteins, thereby preventing neuronal uptake and spread of disease. (A) Astrocytes endocytose free and EV-associated aggregate prone proteins including α-syn and Aβ and process them in the lysosome but subsequent lysosomal dysfunction results in debris-burdened enlarged lysosomes that do not degrade the engulfed material. (B) When exposed to Aβ, astrocytes release EVs that induce apoptosis in neighboring astrocytes. (C) Astrocytes also release EVs enriched in glycosphingolipids (GSLs) that bind monomeric Aβ, promoting oligomerization and plaque formation. (D) Microglia uptake both free and EV-associated aggregate-prone proteins and process them through the endolysosomal system where they are repackaged into EVs that are released and engulfed by neighboring neurons, presenting evidence of neurotoxic propagation from glia to neurons. (E) Microglia degrade endocytosed pathogenic proteins via phagocytosis, clearing aggregate prone proteins.