Apolipoprotein E epsilon 4 triggers neurotoxicity via cholesterol accumulation, acetylcholine dyshomeostasis, and PKCe mislocalization in cholinergic neuronal cells

The Apolipoprotein E (ApoE) has been known to regulate cholesterol and ss-amyloid (A beta) production, redistribution, and elimination, in the central nervous system (CNS). The ApoE epsilon 4 polymorphic variant leads to impaired brain cholesterol homeostasis and amyloidogenic pathway, thus representing the major risk factor for Alzheimer's Disease (AD). Currently, less is known about the molecular mechanisms connecting ApoE epsilon 4-related cholesterol metabolism and cholinergic system degeneration, one of the main AD pathological features. Herein, in vitro cholinergic neuron models were developed in order to study ApoE neuronal expression and investigate the possible interplay between cholesterol metabolism and cholinergic pathway impairment prompted by epsilon 4 isoform. Particularly, alterations specifically occurring in ApoE epsilon 4-carrying neurons (i.e. increased intracellular ApoE, amyloid precursor protein (APP) and A beta levels, elevated apoptosis, and reduced cell survival) were recapitulated. ApoE epsilon 4 expression was found to increase intracellular cholesterol accumulation, by regulating the related gene expression, while reducing cholesterol precursor acetyl-CoA, which in turn fuels the acetylcholine (ACh) synthesis route. In parallel, although the ACh intracellular signalling was activated, as demonstrated by the boosted extracellular ACh as well as increased IP3 and Ca2+, the PKCe activation via membrane translocation was surprisingly suppressed, probably explained by the cholesterol overload in ApoE epsilon 4 neuron-like cells. Consequently, the PKC-dependent anti-apoptotic and neuroprotective roles results impaired, reliably adding to other causes of cell death prompted by ApoE epsilon 4. Overall, the obtained data open the way to further critical considerations of ApoE epsilon 4-dependent cholesterol metabolism dysregulation in the alteration of cholinergic pathway, neurotoxicity, and neuronal death.

Automated summary

The ApoE epsilon 4 polymorphic variant is a major risk factor for Alzheimer's Disease (AD) due to its effects on cholesterol metabolism and cholinergic pathway impairment. In this study, in vitro cholinergic neuron models were used to investigate the interplay between ApoE epsilon 4-related cholesterol metabolism dysregulation and cholinergic system degeneration. The results showed that ApoE epsilon 4 expression led to intracellular cholesterol accumulation and reduced acetylcholine synthesis, resulting in cholinergic pathway impairment and neuronal death.