ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias

Abstract

The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and several other neurodegenerative conditions, including Lewy body dementia (LBD). The three APOE alleles encode protein isoforms that differ from one another only at amino acid positions 112 and 158: apoE2 (C112, C158), apoE3 (C112, R158), and apoE4 (R112, R158). Despite progress, it remains unclear how these small amino acid differences in apoE sequence among the three isoforms lead to profound effects on aging and disease-related pathways. Here, we propose a novel "ApoE Cascade Hypothesis" in AD and age-related cognitive decline, which states that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD. As such, apoE-targeted therapeutic interventions are predicted to be more effective by addressing the biochemical phase of the cascade.

Figure 1.. ApoE cascade hypothesis.

The cascade starts from the different biochemical and biophysical properties including apoE structure, lipidation, protein levels, receptor binding, and oligomerization. These biochemical/biophysical differences are then propagated to functional effects on cellular homeostasis including cellular stress, endosomal-lysosomal trafficking, as well as lipid dysregulation. Not depicted here, some of these cellular effects can be either cell autonomous in cells expressing abundant apoE (astrocytes and microglia in the brain, hepatocytes and macrophages in the periphery, and vascular mural cells interfacing the periphery with the brain), or non-cell autonomous (e.g., secreted apoE from one cell type binding to apoE receptors on another including neurons). These cellular effects are further relayed to trackable phenotypes at the systems level highlighted by neuroinflammation, vascular dysfunction, and neuropathologies, leading to synaptic dysfunction/loss, neurodegeneration, and eventual age-related cognitive decline and AD.

Figure 2.. ApoE amino acid sequence and potential post translational modification sites.

Amino acid sequence of apoE3 is depicted. Key functional regions and residues that differ among apoE isoforms and variants, as well as known or potential posttranslational modification sites are marked.

Figure 3.. ApoE and cellular homeostasis.

ApoE traffics through the secretory pathway as a non-lipidated or lipidated protein into the extracellular space. ABC transporters load membrane and traffic intracellular lipids onto apoE to produce nascent apoE/lipoprotein particles. ApoE-containing lipid particles can undergo further lipid modifications and are taken up by various cells through receptor-mediated endocytosis by binding to apoE receptors. This process supplies cells with diverse lipids including phospholipids and cholesterols necessary to maintain cellular homeostasis and support synaptic integrity and plasticity. The endocytosed particles and their components are transported to lysosome/autophagosome through late endosomes or recycled back to the extracellular space through recycling endosomes. ApoE isoforms impact cellular homeostasis by differentially modulating membrane trafficking, ER stress, and mitochondria function due to their individual effects on protein homeostasis, aggregation, and lipid metabolism.