Author(s): Alessandro Peri [*] 2 , Susanna Benvenuti 1 , Paola Luciani 1 , Cristiana Deledda 1
Alzheimer's disease; cholesterol; estrogens; IGF-1; neurodegeneration; seladin-1
Neurodegenerative disorders include several pathologies, and although each disease has its own peculiar characteristics, most of them affect middle-aged or older people, have a chronic progress and are caused by complex, partially unknown mechanisms that lead to neuronal cell degeneration and death, together with severe impairment in the neuronal communication pathways. The most common neurodegenerative disease in the elderly is Alzheimer's disease (AD), which affects approximately 25 million people worldwide. AD is characterized by extracellular accumulation of [beta]-amyloid (A[beta]) and intracellular deposits of neurofibrillary tangles in specific regions of the brain. Affected patients present a progressive impairment of cognitive functions, such as memory and speech ability, and in advanced stages of the disease they require continuous assistance with basic activities of daily life for survival. Although much progress toward understanding the pathogenic mechanisms of neurodegenerative diseases has been made in recent years, markers that are able to predict or identify these diseases at early stages are still lacking. Furthermore, few effective treatments and no cures are currently available. As a matter of fact, neurodegenerative diseases still represent a public health, social and economic burden worldwide  .
Approximately 10 years ago, a new neuroprotective factor, named seladin-1 (acronym for selective AD indicator-1), was identified  . Since its first description, seladin-1 promised to open new scenarios on the complex relationships involving the endocrine and nervous systems. The seladin-1 gene was found to correspond to the gene encoding the enzyme 3-[beta]-hydroxysterol Δ-24-reductase (DHCR24), which catalyzes the biosynthesis of cholesterol from its precursor desmosterol. There is experimental evidence that the amount of cell cholesterol plays a fundamental role in brain homeostasis. It has been demonstrated that expression of the seladin-1 gene is stimulated by estrogens and IGF-1, which are known to exert protective effects on the brain. The apparent close link between the neuroprotective properties of seladin-1 on one hand, and of estrogens and IGF-1 on the other hand, led us to hypothesize that the newly described protein might be a mediator of the neuroprotective effects of these hormones, and that cholesterol might be the common link. The main objective of this review is to present an up-to-date report of the studies that addressed this issue.
Cholesterol & AD
There are epidemiological and experimental data that suggest a role for cholesterol in the pathogenesis of AD. It is, for instance, well known that the ε4 allelic variant of APOE represents a major genetic risk factor for AD. APOE is transported with cholesterol and its isoforms have different transport efficiency. APOE binds A[beta] in an isoform-specific manner and is involved in the clearance of A[beta]. APOE4 alleles are associated with increased A[beta] accumulation  . However, the role of cholesterol in the brain still represents an open and controversial issue. Experimental data from in vitro systems and animal models of AD showed, for example, that high cholesterol levels favor A[beta] formation [3,4] . In agreement with these findings,...