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.

Abnormal Lipid Accumulation and Cluster Formation of Naive Peripheral Blood Mononuclear Cells: A Useful Tool for Early Detection of Central Nervous System Damage in Elderly

“…The control subjects, cognitively healthy and free of any neurological or psychiatric illnesses, had minimal NL content changes in their PBMCs, as previously reported by us [2][3][4]32]. Interestingly, NL content was significantly correlated to clinical severity, as assessed by MMSE [2][3][4]32]. These results led us to hypothesize that NL changes in PBMCs might reflect dynamic modifications in cholesterol homeostasis, which occur in the brain during early development of cognitive deficit [2][3][4]32].…”

“…These changes have also been observed in MCI, but with less magnitude and extent. The control subjects, cognitively healthy and free of any neurological or psychiatric illnesses, had minimal NL content changes in their PBMCs, as previously reported by us [2][3][4]32]. Interestingly, NL content was significantly correlated to clinical severity, as assessed by MMSE [2][3][4]32].…”

“…Interestingly, NL content was significantly correlated to clinical severity, as assessed by MMSE [2][3][4]32]. These results led us to hypothesize that NL changes in PBMCs might reflect dynamic modifications in cholesterol homeostasis, which occur in the brain during early development of cognitive deficit [2][3][4]32]. Another interesting finding of this study was that PBMCs from dementia and MCI groups, freshly isolated from buffy coat and plated in 6-well tissue culture dishes, merged together to form large aggregates or clusters, which are visible under light microscope.…”

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.…”

The role of small GTPase Rac1 in stress signaling

“…Chol is essential component of rafts, it is found in double amount in rafts compared with PMs (Pike 2009). It serves as cofactor for signaling molecules and as precursor for steroid hormones (Anchisi et al 2012). Chol is required for forming L o phases in model membranes (Goni et al 2009).…”