- Alzheimer's disease (AD) is the most common form of dementia in older adults. Currently, there is no cure for AD. The hallmark of AD is the accumulation of extracellular amyloid plaques composed of amyloid-β (Aβ) peptides (especially Aβ1-42) and neurofibrillary tangles, composed of hyperphosphorylated tau and accompanied by chronic neuroinflammation. Aβ peptides are derived from the amyloid precursor protein (APP). The oligomeric form of Aβ peptides is probably the most neurotoxic species; its accumulation eventually forms the insoluble and aggregated amyloid plaques.
- In the last decade, it has become obvious that Alzheimer's disease (AD) is closely linked to changes in lipids or lipid metabolism. One of the main pathological hallmarks of AD is amyloid-β (Aβ) deposition. Aβ is derived from sequential proteolytic processing of the amyloid precursor protein (APP). Interestingly, both, the APP and all APP secretases are transmembrane proteins that cleave APP close to and in the lipid bilayer. Moreover, apoE4 has been identified as the most prevalent genetic risk factor for AD.
- Identified in 1993, APOE4 is the greatest genetic risk factor for sporadic Alzheimerŉs disease (AD), increasing risk up to 15-fold compared with APOE3, with APOE2 decreasing AD risk. However, the functional effects of APOE4 on AD pathology remain unclear and, in some cases, controversial. In vivo progress to understand how the human (h)-APOE genotypes affect AD pathology has been limited by the lack of a tractable familial AD-transgenic (FAD-Tg) mouse model expressing h-APOE rather than mouse (m)-APOE.
- The role of APOE in the risk of Alzheimer's disease (AD) has largely focused on its effects on AD pathological processes. However, there are increasing data that APOE genotype affects processes in normal brains. Studies of young cognitively normal humans show effects of APOE genotype on brain structure and activity. Studies of normal APOE knock-in mice show effects of APOE genotype on brain structure, neuronal markers, and behavior. APOE interactions with molecules important for lipid efflux and lipid endocytosis underlie effects of APOE genotype on neuroinflammation and lipoprotein composition.
- The LDL receptor (LDLR) family has long been studied for its role in cholesterol transport and metabolism; however, the identification of ApoE4, an LDLR ligand, as a genetic risk factor for late-onset Alzheimer's disease has focused attention on the role this receptor family plays in the CNS. Surprisingly, it was discovered that two LDLR family members, ApoE receptor 2 (Apoer2) and VLDL receptor (Vldlr), play key roles in brain development and adult synaptic plasticity, primarily by mediating Reelin signaling.
- ApoE is a multifunctional protein that is expressed by many cell types that influences many aspects of cardiovascular physiology. In humans, there are three major allelic variants that differentially influence lipoprotein metabolism and risk for the development of atherosclerosis. Apoe-deficient mice and human apoE isoform knockin mice, as well as hypomorphic Apoe mice, have significantly contributed to our understanding of the role of apoE in lipoprotein metabolism, monocyte/macrophage biology, and atherosclerosis.