Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

Abstract

One of the primary genetic risk factors for Alzheimer's disease (AD) is the presence of the Ɛ4 allele of apolipoprotein E (APOE). APOE is a polymorphic lipoprotein that is a major cholesterol carrier in the brain. It is also involved in various cellular functions such as neuronal signaling, neuroinflammation and glucose metabolism. Humans predominantly possess three different allelic variants of APOE, termed E2, E3, and E4, with the E3 allele being the most common. The presence of the E4 allele is associated with increased risk of AD whereas E2 reduces the risk. To understand the molecular mechanisms that underlie APOE-related genetic risk, considerable effort has been devoted towards developing cellular and animal models. Data from these models indicate that APOE4 exacerbates amyloid β plaque burden in a dose-dependent manner. and may also enhance tau pathogenesis in an isoform-dependent manner. Other studies have suggested APOE4 increases the risk of AD by mechanisms that are distinct from modulation of Aβ or tau pathology. Further, whether plasma APOE, by influencing systemic metabolic pathways, can also possibly alter CNS function indirectly is not complete;y understood. Collectively, the available studies suggest that APOE may impact multiple signaling pathways and thus investigators have sought therapeutics that would disrupt pathological functions of APOE while preserving or enhancing beneficial functions. This review will highlight some of the therapeutic strategies that are currently being pursued to target APOE4 towards preventing or treating AD and we will discuss additional strategies that holds promise for the future.

Redox signaling and Alzheimer’s disease: from pathomechanism insights to biomarker discovery and therapy strategy

“…Cholesterol homeostasis was impaired in AD as well [20]. One of the primary risk factors for AD is the presence of apolipoprotein E (APOE), a polymorphic lipoprotein that mainly carries cholesterol in the brain [21]. There are three major APOE alleles in humans, among which APOE 2 allele is closely associated with the reduced risk of AD, while APOE 4 allele devotes much to AD occurrence [22].…”

APOE2 is associated with longevity independent of Alzheimer’s disease

“…While apoE isoforms can directly affect Alzheimer’s neuropathology, including the accumulation of amyloid-β (Aβ) and tau, increasing evidence has demonstrated that apoE isoforms also contribute to cognitive function through AD neuropathology-independent pathways ( Liu et al, 2013 ; M. Di Battista et al, 2016 ; Montagne et al, 2020 ; Yamazaki et al, 2020 ). These effects might be mediated by apoE-regulated lipid metabolism, synaptic function, vascular integrity, and/or neuroinflammation ( Liu et al, 2013 ; M. Di Battista et al, 2016 ; Montagne et al, 2020 ; Yamazaki et al, 2020 ; Williams et al, 2020 ; Najm et al, 2019 ). Recently, by performing both clinical and preclinical analysis, we showed that APOE2 protects against age-associated cognitive decline independent of AD neuropathology.…”

Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer’s disease

“…These studies with the MMP9KO mice provide a simplified view of the deleterious actions of MMP-9 in AD and the benefits associated with inhibiting it, without the complexity of apoE ~ 137 ~ isoforms. However, apoE-driven AD pathologies differ from pure amyloid pathologies [525], [526] and, as detailed in this thesis, apoE can modulate multiple aspects of MMP-9 regulation other than elevated expression and may still influence MMP-9 disposition after its induction. Hence, it would be interesting to build on these in vivo studies and cross MMP9KO mice with EFAD mice, to generate EFAD mice in which the MMP-9 gene is deleted.…”