Cholesterol in brain disease: sometimes determinant and frequently implicated

Abstract

Cholesterol is essential for neuronal physiology, both during development and in the adult life: as a major component of cell membranes and precursor of steroid hormones, it contributes to the regulation of ion permeability, cell shape, cell-cell interaction, and transmembrane signaling. Consistently, hereditary diseases with mutations in cholesterol-related genes result in impaired brain function during early life. In addition, defects in brain cholesterol metabolism may contribute to neurological syndromes, such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), and even to the cognitive deficits typical of the old age. In these cases, brain cholesterol defects may be secondary to disease-causing elements and contribute to the functional deficits by altering synaptic functions. In the first part of this review, we will describe hereditary and non-hereditary causes of cholesterol dyshomeostasis and the relationship to brain diseases. In the second part, we will focus on the mechanisms by which perturbation of cholesterol metabolism can affect synaptic function.

ABCA1‐Mediated Cholesterol Efflux Capacity to Cerebrospinal Fluid Is Reduced in Patients With Mild Cognitive Impairment and Alzheimer's Disease

“…The human brain is the largest repository of cholesterol in the body,1 so, not surprisingly, cholesterol homeostasis altered in the pathology of Alzheimer's disease (AD) 2. Adding to this unique lipid environment is the synthesis of cholesterol within the brain, predominantly in glial cells, without significant import from the liver 3.…”

Molecular rheology of neuronal membranes explored using a molecular rotor: Implications for receptor function

“…Interestingly, cellular membranes in the nervous system are characterized by very high concentration and remarkable diversity of lipids, and these are correlated with increased complexity in the function of the nervous system (Sastry, 1985;Wenk, 2005). In this context, cholesterol represents an important lipid since brain cholesterol has been implicated in a number of neurological disorders (Chattopadhyay and Paila, 2007;Martín et al, 2014), some of which share a common etiology of defective cholesterol 4 metabolism in the brain (Porter and Herman, 2011). More importantly, the function of neuronal receptors depends on cholesterol (Pucadyil and Chattopadhyay, 2006;Allen et al, 2007;Paila and Chattopadhyay, 2010;Jafurulla and Chattopadhyay, 2013), which affects neurotransmission, resulting in mood and anxiety disorders (Papakostas et al, 2004).…”

Statins and Cholesterol: A Perspective Revisited

“…[37] Most of the knowledge about a molecule is gained through experimental studies and following are some of studies which have dissected role of cholesterol in brain cells e.g., transgenic mice over-expressing Cyp46 displayed increased expression of synaptic proteins and improved spatial memory; [38] cholesterol depletion impairs synaptic vesicle exocytosis in cultured neurons; cholesterol depletion impairs endocytosis due to destabilization surface AMPA receptors; [39] cholesterol depletion impairs long-term potentiation due to destabilization surface NMDA receptors [40] etc.…”