Altered Cholesterol Intracellular Trafficking and the Development of Pathological Hallmarks of Sporadic AD

Abstract

Compared to the rare familial early onset Alzheimer's disease (AD) that results from gene mutations in AbPP and presenilin-1, the pathogenesis of sporadic AD is much more complex and is believed to result from complex interactions between nutritional, environmental, epigenetic and genetic factors. Among those factors, the presence APOE4 is still the single strongest genetic risk factor for sporadic AD. However, the exact underlying mechanism whereby apoE4 contributes to the pathogenesis of sporadic AD remains unclear. Here, we discuss how altered cholesterol intracellular trafficking as a result of apoE4 might contribute to the development of pathological hallmarks of AD including brain deposition of amyloid beta (Ab), neurofibrillary tangles, and synaptic dysfunction.

Keywords: Alzheimer’s disease; ApoE4; Cholesterol; Niemann-Pick type C disease.

Figure 1. Cholesterol homeostasis in brain

Brain cholesterol is almost completely dependent on in situ synthesis of HDL-like apoE-cholesterol by astrocytes. Such HDL-like apoE-cholesterol supplies the neuronal need of cholesterol via receptor-mediated endocytosis, a process where apoE-cholesterol bound to their receptors are internalized, transported to endolysosomes, hydrolyzed to free cholesterol, and from where free cholesterol is transported to various intracellular compartments (ER, Golgi) or plasma membrane via a mechanism involving the Niemann-Pick type C proteins type-1 and -2 proteins.

Figure 2. ApoE4-induced cholesterol dyshomeostasis

ApoE-cholesterol is up-taken by neurons via receptor-mediated endocytosis with the assistance of LDLRs. Different apoE isoforms have different affinities for lipids and receptors for cholesterol uptake, and the associations between cholesterol and different apoE can result in drastic differences in endocytic trafficking and distribution of cholesterol in neurons. ApoE4 could lead to impaired recycling of cholesterol back to ER, Golgi and plasma membranes, where cholesterol is needed for membrane repair, neurite outgrowth, and synaptic plasticity. In addition, apoE4 could increase accumulation of cholesterol in endolysosomes thus disturbing endolysosome function.

Figure 3. ApoE4-cholesterol contributes to the development of AD pathology

ApoE4 could promote AβPP internalization or impair recycling of internalized AβPP, and thus to leads enhanced amyloidgenic processing of AβPP in endosome, the site where BACE-1 and γ-secretase are almost exclusively located and active in the acidic environment. Another mechanism whereby apoE4 promotes Aβ generation might result from apoE4-induced endolysosome cholesterol accumulation and endolysosome dysfunction, which could enhance Aβ generation in endosomes and inhibit Aβ degradation in lysosomes. Because hyperphosphorylated tau can be degraded in autophagosomes-lysosomes, apoE4-induced cholesterol accumulation in endolysosome and subsequent endolysosome dysfunction could impair tau degradation in autophagosome-lysosomes, thus leading to increased accumulation of hyperphosphorylated tau and the development of neurofibrillary tangle.