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.

The objective of this review was to focus on recent studies indicating how deregulation of lipid metabolism may be of particular importance for central nervous system (CNS) injuries and neurodegenerative disorders. Furthermore, since an accumulation of neutral lipids (NLs), mainly cholesterol esters (CEs) in the form of cytoplasmic lipid droplets was previously found by our group in peripheral blood mononuclear cells (PBMCs) of Alzheimer (AD) patients and their first degree relatives (AD-FDR), we reviewed current data providing evidence that altered lipid metabolism in brain can also affect cholesterol metabolism in the systemic circulation. Using data from literature we proposed a mechanistic model that helps us to explain why subjects with neurological disorders often accumulate NLs in their PBMCs. If validated by future research, it should provide a rationale for NL-PBMCs determination by Oil Red O (ORO) staining method as a useful tool for diagnostic and therapeutic interventions in AD and possibly in other forms of dementia occurring in childhood as well as in elderly.

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