Amyloid beta accumulation in HIV-1 infected brain: the role of altered cholesterol homeostasis.

Abstract

The long-term survival of HIV-1 infected individuals credited to the availability and use of effective antiretroviral therapy (ART) is unfortunately now accompanied by an almost 50% prevalence of HIV-1 associated neurocognitive disorder (HAND). Increasingly, it has been realized that HIV-1 infected people on ART have clinical and pathological observations of Alzheimer's disease (AD)-like manifestations including neurocognitive problems, intraneuronal accumulation of amyloid beta (Aβ) protein, and disturbed synaptic integrity. Part of the current challenge facing the medical community and people living with HIV-1 infection is that the pathogenesis of HAND remains unclear, and little is known about how AD-like pathology is developed as a result of HIV-1 infection and/or long-term ART treatment. Here we discuss the potential role of altered plasma cholesterol homeostasis, a prominent feature of HIV-1 infection, on the development of intraneuronal Aβ accumulation in HIV-1 infected brain. We speculate that elevated plasma LDL cholesterol, once it enters brain parenchyma via an increasingly leaky BBB, can be internalized by neurons via receptor-mediated endocytosis, a process that could promote internalization of amyloid beta precursor protein (AβPP). Unlike brain in situ synthesized apoE-cholesterol, apoB-containing LDL-cholesterol could lead to cholesterol accumulation thus disturbing neuronal endolysosome function and ultimately the accumulation of intraneuronal Aβ in HIV-1 infected brain.