ApoE and ApoE Receptors in Brain Amyloid Beta Clearance
Dr. Bu's Neurobiology of Alzheimer's Disease Lab is focused on investigating the roles of two classes of receptors, the low-density lipoprotein receptor (LDLR) family and cell surface heparan sulfate proteoglycans (HSPGs), in regulating the metabolism of amyloid beta (abeta) peptides and apolipoprotein E (apoE). The accumulation, aggregation and deposition of abeta peptides generated through proteolytic cleavage of amyloid precursor protein (APP) are likely the initiating events in the pathogenesis of Alzheimer's disease (AD). Increasing evidence indicates that impaired clearance of abeta is responsible for late-onset AD, which represents the vast majority of AD cases.
While transporting cholesterol is a primary function, apoE also regulates abeta metabolism and aggregation. Although earlier work suggests that different affinities of apoE isoforms to abeta might account for their effects on abeta clearance, recent studies indicate that apoE also competes with abeta for cellular uptake through apoE receptors. Using cellular and animal models combined with human studies, the lab investigates the complex mechanisms underlying isoform-dependent effects of apoE in normal central nervous system functions, abeta clearance, abeta pathology and cognition during aging and AD.
ApoE and LRP1 in Abeta Clearance
While overproduction of abeta due to mutations in the amyloid precursor protein (APP) and presenilin 1(PSEN1) and presenilin 2 (PSEN2) genes is the primary cause of early-onset AD, increasing evidence indicates that impaired brain abeta clearance, perhaps in conjunction with other pathogenic insults, is likely the major driver for late-onset AD. Using conditional knockout mouse models crossed with amyloid model mice, Dr. Bu's lab has demonstrated that the low-density lipoprotein receptor-related protein 1 (LRP1), a major receptor for both apoE and abeta, plays essential roles in brain abeta clearance. These studies have not only demonstrated a critical role of LRP1 in abeta clearance but have also highlighted the importance of various brain cell types, including neurons, glia, smooth muscle cells and pericytes, in the process of brain abeta clearance.
Dr. Bu's lab further postulated that since abeta is mainly generated by neurons, these cells are predicted to have the highest risk of encountering abeta among all cell types in the brain. However, in the published literature it was still unclear whether they are also involved in abeta clearance. Recently, the lab showed that receptor-mediated endocytosis in neurons by LRP1 also plays a critical role in brain abeta clearance.
Using their unique mouse models, lab researchers demonstrated that conditional knockout of LRP1 in mouse forebrain neurons leads to increased brain abeta and exacerbated amyloid plaque deposition selectively in the cortex of amyloid model mice without affecting abeta production. The lab hypothesizes that disturbed abeta clearance is likely due to the suppression of LRP1-mediated neuronal abeta uptake and degradation. Significantly, these results demonstrate that LRP1 plays an important role in receptor-mediated clearance of abeta and indicate that neurons not only produce but also clear abeta. Further understanding of the mechanisms underlying LRP1-mediated abeta clearance in brain parenchyma and along the vasculature should enable the rational design of novel diagnostic and ART-20260734- therapeutic strategies for AD.
APOE, HSPGs and Abeta Clearance
HSPGs are abundant cell surface receptors that co-localize with amyloid plaques. Recently, the Neurobiology of Alzheimer's Disease Lab has shown that genetically engineered mice lacking heparan sulfates (HS) in forebrain neurons were protected from amyloid deposition because of a faster clearance of abeta and reduction in abeta aggregation. Importantly, it was shown that several HSPG species are increased in human AD postmortem brain tissue. These findings suggest that targeting abeta-HSPG interactions might be an effective strategy for AD prevention and treatment.