[“Molecule Man

SLOS is characterized by multiple developmental abnormalities, such as distinctive facial features, limb malformations, microcephaly, cleft palate, polydactyly and holoprosencephaly, as well as severe intellectual impairment. Because plasma cholesterol levels are very low in individuals with SLOS, a treatment currently used for the disease is based on the idea of normalizing the level of cholesterol in plasma by feeding affected individuals a cholesterolrich diet. Although studies in which this protocol was used involved only small numbers of patients, some anecdotal reports suggest that this treatment might be beneficial.It is not clear, however, why increasing the level of plasma cholesterol would improve the neurological phenotype, because plasma lipoproteins, and the cholesterol carried therein, do not cross the bloodbrain barrier or enter the CNS. It is also unclear whether the developmental and neurological abnormalities in individuals with SLOS are caused by the low level of cholesterol in the brain or by the abnormal accumulation of the potentially toxic cholesterol precursor, dehydrocholesterol.In support of the latter, mice that lack the cholesterol regulatory protein INSIG exhibit severe facial clefting and have developmental abnormalities that are very similar to those that occur in individuals with SLOS.Because INSIG knockout mice have uncontrolled, high rates of cholesterol synthesis, and a {|Targetmol’s {Endurobol|Amiodarone cellular buildup of cholesterol precursors such as dehydrocholesterol, these data suggest that the accumulation of dehydrocholesterol, rather than the deficiency of cholesterol, is the cause of at least some of the pathophysiological abnormalities in SLOS.The developmental abnormalities in individuals with SLOS might also be caused by reduced functioning of the sonic hedgehog signaling pathway, which is required for normal embryonic development of the CNS, limbs and facial features. An important component of this pathway is the SHH protein, whose activity requires the covalent attachment of a cholesterol molecule to the protein. The accumulation of A plaques and the loss of neurons, particularly in the hippocampus, are thought to be central events in the development of AD. The deposition of A reflects the balance between the production and removal of A peptides from the brain.Consequently, either overproduction or impaired clearance of A, or a combination of both processes, probably plays a key role in the pathophysiology of AD.When APP is cleaved by secretase, nonamyloidogenic products are generated that do not cause abnormal brain pathology.Some of the mechanisms proposed for A degradation are discussed below. In contrast to NPC disease and SLOS, no direct causal relationship has been established between AD and the dysregulation of cholesterol metabolism.Thus, although some experimental evidence indicates that alterations in cholesterol metabolism in the brain might contribute to the pathogenesis of AD, it is not clear whether the modification of cholesterol homeostasis in AD brains is a cause or consequence of the disease.The and secretases that generate the A peptides from APP are predominantly localized to cholesterolenriched microdomains of the plasma membrane. Several in vitro and in vivo experiments have demonstrated that the cellular concentration of cholesterol can regulate the production and amount of the A peptides.For example, a decreased level of cellular cholesterol increases secretase cleavage of APP, thereby decreasing the processing of APP into the toxic A peptides that accumulate in amyloid plaques.

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