Cholesterol homeostasis: a key to prevent or slow down neurodegeneration

Abstract

Neurodegeneration, a common feature for many brain disorders, has severe consequences on the mental and physical health of an individual. Typically human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people, progress slowly, and lead to disability and premature death; however they may occur at all ages. Despite extensive research and investments, current therapeutic interventions against these disorders treat solely the symptoms. Therefore, since the underlying mechanisms of damage to neurons are similar, in spite of etiology and background heterogeneous, it will be of interest to identify possible trigger point of neurodegeneration enabling development of drugs and/or prevention strategies that target many disorders simultaneously. Among the factors that have been identified so far to cause neurodegeneration, failures in cholesterol homeostasis are indubitably the best investigated. The aim of this review is to critically discuss some of the main results reported in the recent years in this field mainly focusing on the mechanisms that, by recovering perturbations of cholesterol homeostasis in neuronal cells, may correct clinically relevant features occurring in different neurodegenerative disorders and, in this regard, also debate the current potential therapeutic interventions.

Keywords: cholesterol esterification; cholesterol homeostasis; drug targets; neurodegenerative disorders; neuronal membranes.

Figure 1

Alzheimer's disease (AD). AD is a progressive neurologic disease of the brain leading to the irreversible loss of neurons and the loss of intellectual abilities, including memory, and reasoning, which become severe enough to impede social or occupational functioning. Although scientists are still trying to fully understand the cause/s of AD, the formation of amyloid β (Aβ) protein positive neuritic plaques is considered one of the most important characteristic of AD so much so that Aβ deposition in the brain is used to diagnose the disease in autopsy. Aβ peptides are fragments from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. They are generated in the amyloidogenic pathway (B) of APP processing by sequential proteolysis by β- (BACE1) and γ-secretases. In the alternative non-amyloidogenic APP processing pathway (A), α-secretase cleaves within the Aβ peptide region and prevents Aβ generation.

Figure 2

The prion diseases (PrD). PrD are a large group of related neurodegenerative conditions, which affect both animals and humans. Included are Creutzfeldt–Jakob disease and Gerstmann-Strãussler-Scheinker in humans, bovine spongiform encephalopathy, or “mad cow disease” in cattle, chronic wasting disease in mule deer and elk, and scrapie in sheep. Prion diseases are unique in that they can be inherited, can occur sporadically, or can be infectious. The infectious agent in the PrD is composed mainly or entirely of an abnormal conformation of a host-encoded glycoprotein called the prion protein (PrPc). The replication of prions implies the transformation of the normal version of this protein PrPc into a misfolded form (PrPsc). An increased concentration of PrPc at the membrane leads to a structural transition toward abnormal intermolecular beta sheet. This dimerization could well be the initial step on the pathway of the conversion into PrPSc.

Figure 3

Cholesterol homeostasis (steady state). Differently from the most tissues that take up cholesterol from circulating plasma lipoproteins through the classic mechanism of the low density lipoprotein receptor (LDLR), due to the BBB, brain does not have direct access to cholesterol carried by plasma lipoproteins and therefore, it meets its cholesterol needs through de novo synthesis mainly in glial cells, with only a small amount of cholesterol synthesized in neurons. Glial cells package neo-synthesized cholesterol into Apo E—containing lipoprotein particles, which in turn are secreted into the CSF through the ATP-binding cassette transporter 1 (ABCA1). Apo E-containing lipoproteins are then taken up by neurons and FC released is transported for subsequent metabolism and trafficking to other intracellular sites. Neurons keep constant their cholesterol concentrations through the same homeostatic mechanisms regulating the intracellular cholesterol metabolism in peripheral tissues: cholesterol synthesized in the ER, as well as that released by Apo E—containing lipoprotein catabolism, moves to PMs, in part, by interacting with Cav-1. Once the capacity of PMs and other compartments to absorb cholesterol is exceeded, cholesterol is transported back to the ER, where, in a small part it is esterified by ACAT and accumulated as lipid droplets. The large part of excess cholesterol, however, is converted into 24S-OHC, crosses the BBB, enters the plasma, and is delivered to the liver for excretion into bile.

Figure 4

Cholesterol homeostasis (neurodegenerative disorders). An imbalance of one or more of finely regulated homeostatic mechanisms that lead to even modest changes in ER-FC pool in neurons can cause a serious and sometimes fatal neurologic disorder. Namely, if a reduction in the transport of cholesterol between ER and PM occurs as a consequence of genetic and/or environmental factors, neuronal ER-FC increases. This increase may cause the activation of ACAT1 leading to an increased CE synthesis while reducing the distribution of FC in raft-domains. If these alterations persist over time the consequences may be: rafts disassembly, demyelination, alterations in synapse formation and function, in other words, neurodegeneration. Beside ACAT1 activation, an increase in ER cholesterol pool of neurons may also activate the CYP46A1 thereby enhancing the levels of circulating 24S-OHC. This is an oxygenated derivative of cholesterol able to cause lipoprotein oxidation (ox-LP). With a mechanism similar to that described for atherosclerosis, ox-Lp might be recognized by scavenger receptors (SR) on the surface of white blood cells, which in turn may be engorged with CE and become foam cells.