Review: ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies

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BrianR
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Review: ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies

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Open access review paper. I found it to be more clearly written than similarly detailed APOE-related papers.

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-022-00574-4


ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Ana-Caroline Raulin, Sydney V. Doss, Zachary A. Trottier, Tadafumi C. Ikezu, Guojun Bu & Chia-Chen Liu
Molecular Neurodegeneration volume 17, Article number: 72 (2022). 8 November 2022
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia worldwide, and its prevalence is rapidly increasing due to extended lifespans. Among the increasing number of genetic risk factors identified, the apolipoprotein E (APOE) gene remains the strongest and most prevalent, impacting more than half of all AD cases. While the ε4 allele of the APOE gene significantly increases AD risk, the ε2 allele is protective relative to the common ε3 allele. These gene alleles encode three apoE protein isoforms that differ at two amino acid positions.

The primary physiological function of apoE is to mediate lipid transport in the brain and periphery; however, additional functions of apoE in diverse biological functions have been recognized.

Pathogenically, apoE seeds amyloid-β (Aβ) plaques in the brain with apoE4 driving earlier and more abundant amyloids. ApoE isoforms also have differential effects on multiple Aβ-related or Aβ-independent pathways.

The complexity of apoE biology and pathobiology presents challenges to designing effective apoE-targeted therapeutic strategies. This review examines the key pathobiological pathways of apoE and related targeting strategies with a specific focus on the latest technological advances and tools.
And their thoughts on a frequently asked question: Why do we even have APOE?
Physiological function of apoE
ApoE is abundantly expressed in the periphery and in the CNS. However, due to the BBB, apoE in the periphery and in the CNS exist as distinct pools [53]. Therefore, it is critical to consider the independent role that each may play in AD pathogenesis, and the opportunity presented by each for therapeutic intervention. ApoE in the periphery is predominantly produced by the liver [32]. Peripheral apoE maintains lipid homeostasis by participating in the redistribution and metabolism of lipids, such as triglycerides, cholesterol, cholesteryl esters, and phospholipids, through the formation of lipoprotein particles. ApoE isoforms have been shown to be differentially associated with peripheral lipoprotein particles. For instance, apoE4 is mostly found in triglyceride-rich particles like chylomicrons and very low-density lipoproteins (VLDL), whereas apoE2 and apoE3 have preference to the high-density lipoproteins (HDL). Thus, the single Arg to Cys amino-acid substitution at position 112 dictates the differential distribution of apoE isoforms among lipoprotein particles [54]. Single amino acid substitutions in rare apoE isoforms may also modulate their distribution among peripheral lipoproteins. For instance, apoE3-Jac exhibits higher cholesterol efflux capacity compared to apoE3, suggesting that apoE3-Jac may differentially bind lipids and could be differentially distributed among lipoprotein particles compared to the common apoE isoforms. Peripheral apoE is also important for cardiovascular function and immune modulation, both factors that contribute to AD risk [20, 55]. These effects will be discussed in more detail later in this review.

In the CNS, apoE-mediated cholesterol and lipid transport plays a critical role in synapse formation and tissue repair [5]. It also plays a role in neurite outgrowth following injury in an isoform dependent manner with astrocytic apoE3 inducing greater neurite outgrowth than astrocytes secreting apoE4 [56]. Human apoE4-targeted replacement (TR) mice, as well as human APOE4 carriers, show a reduction in dendritic spine density even in the absence of disease pathology [57]. This is consistent with studies which revealed that apoE4 alters structural reorganization of neurons [58], reduces expression of key synaptic proteins [59], and inhibits glutamatergic signaling which are critical for neuronal plasticity and network maintenance [60].

Emerging evidence shows that the function of apoE is largely cell type-specific [61, 62]. While apoE expression in the brain was first described in astrocytes, it has been found to be drastically up regulated in activated microglia and in stressed neurons under pathological conditions and injury [34, 36, 63, 64]. Recent reports also suggest that primary astrocytes and microglia express and secrete apoE with varying sizes likely due to different post-translational modifications and lipid compositions, which might contribute to cell type-specific functions in response to injury [65]. Other cell types, such as pericytes and oligodendrocytes, have also been reported to express apoE more abundantly after liver X receptor (LXR) stimulation and after injury [66,67,68,69]. Thus, exploring the structure, lipidation status, and biochemical properties of apoE isoforms expressed by individual brain cell types will be critical for understanding apoE-related effects in the brain.
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