HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

Abstract

The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer’s disease (AD). Alzheimer’s disease is characterized by the accumulation of extracellular amyloid beta (Aβ) and abnormally hyperphosphorylated intracellular tau filaments in neurons. Cholesterol metabolism has been extensively implicated in the pathogenesis of AD through biological, epidemiological, and genetic studies, with the APOE gene being the most reproducible genetic risk factor for the development of AD. This manuscript explores how HDL-mediated cholesterol is transported in the CNS, with a special emphasis on its relationship to Aβ peptide accumulation and apolipoprotein E (ApoE)-mediated cholesterol transport. Indeed, we reviewed all existing works exploring HDL-like-mediated cholesterol efflux and cholesterol uptake in the context of AD pathogenesis. Existing data seem to point in the direction of decreased cholesterol efflux and the impaired entry of cholesterol into neurons among patients with AD, which could be related to impaired Aβ clearance and tau protein accumulation. However, most of the reviewed studies have been performed in cells that are not physiologically relevant for CNS pathology, representing a major flaw in this field. The ApoE4 genotype seems to be a disruptive element in HDL-like-mediated cholesterol transport through the brain. Overall, further investigations are needed to clarify the role of cholesterol trafficking in AD pathogenesis.

Cellular cholesterol loss by DHCR24 knockdown leads to Aβ production by changing APP intracellular localization

“…There is growing interest in the potential role of cholesterol in the pathogenesis of AD. Very importantly, genetic evidences from the inherited AD animals and patients, such as APOE4 allele, obviously supports that cellular cholesterol deficiency is associated with Aβ production and accumulation ( 4 ). Consistent with our present findings, increasing data reveal that cellular cholesterol deficiency could be involved in Aβ generation, tau hyperphosphorylation, apoptosis, synaptic injuries, inflammation, and autophagy ( 3 , 4 , 5 , 57 , 58 , 59 )).…”

“…A tight link between Alzheimer’s disease (AD) pathology and lipids was already observed more than a century ago by Alois Alzheimer, who described a higher occurrence of “lipoid granules” in postmortem AD-brain tissue as a third pathological hallmark of the disease ( 1 , 2 ). Moreover, accumulating biological, epidemiological, and genetic studies showed that cholesterol loss prevalently involved in AD pathogenesis, including tau pathology, apoptosis, and synaptic injuries, and inhibition of autophagy ( 3 , 4 , 5 ). However, in terms of amyloid-β (Aβ) generation, a well-recognized pathological feature in AD, the vast majority of the cell culture studies have reported that elevated cellular cholesterol level increases Aβ production ( 6 , 7 , 8 , 9 ).…”

“…Only a few evidences suggested that decreased cholesterol level promotes Aβ generation ( 10 , 11 ). Given that enormous evidence of other AD pathologies supported that cholesterol shortage may contribute to the development of AD ( 3 , 4 , 5 ), the divergent view of cholesterol in Aβ encourages a reconsideration of how cholesterol affects Aβ metabolism.…”

“…Furthermore, these genic alterations easily lead to the decrease of cholesterol transport or uptake and blockade of intracellular cholesterol trafficking, resulting in cellular cholesterol deficiency/loss ( 12 , 13 , 14 , 15 , 16 ). What’s more, genetic data strongly suggest that cellular cholesterol deficiency could contribute to AD pathology, such as Aβ production and deposit, tau protein accumulation, and synaptic impairment ( 3 , 4 , 5 , 10 , 11 ). In view of apparent contradictory findings of previous researches, the role of cholesterol in processing of amyloid precursor protein (APP) comes under close scrutiny: does high or low cellular cholesterol level contribute to Aβ generation ( 17 , 18 )?…”

PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer’s Disease

“…The transport of cholesterol from astrocytes to neurons occurs through peculiar lipoprotein particles, similar to plasma HDL [ 23 ]. Specifically, cholesterol and apoE newly produced by astrocytes are secreted and assembled in HDL-like particles which, after remodeling and maturation, finally deliver cholesterol to neurons through the apoE-recognizing receptors mentioned above [ 11 , 24 ].…”