[Abstract unavailable

No abstract

A hallmark of all forms of Alzheimer's disease (AD) is an abnormal accumulation of the beta-amyloid protein (Abeta) in specific brain regions. Both the generation and clearance of Abeta are regulated by cholesterol. Elevated cholesterol levels increase Abeta in cellular and most animals models of AD, and drugs that inhibit cholesterol synthesis lower Abeta in these models. Recent studies show that not only the total amount, but also the distribution of cholesterol within neurons, impacts Abeta biogenesis. The identification of a variant of the apolipoprotein E (APOE) gene as a major genetic risk factor for AD is also consistent with a role for cholesterol in the pathogenesis of AD. Clinical trials have recently been initiated to test whether lowering plasma and/or neuronal cholesterol levels is a viable strategy for treating and preventing AD. In this review, we describe recent findings concerning the molecular mechanisms underlying the cholesterol-AD connection.

The pathogenic event common to all forms of Alzheimer's disease is the abnormal accumulation of the amyloid beta-peptide (Abeta). Here we provide strong evidence that intracellular cholesterol compartmentation modulates the generation of Abeta. Using genetic, biochemical and metabolic approaches, we found that cholesteryl-ester levels are directly correlated with Abeta production. Acyl-coenzyme A:cholesterol acyltransferase (ACAT), the enzyme that catalyses the formation of cholesteryl esters, modulates the generation of Abeta through the tight control of the equilibrium between free cholesterol and cholesteryl esters. We also show that pharmacological inhibitors of ACAT, developed for the treatment of atherosclerosis, are potent modulators of Abeta generation, indicating their potential for use in the treatment of Alzheimer's disease.

The lipid second messenger ceramide regulates several biochemical events that occur during aging. In addition, its level is highly elevated in the amyloid-burdened brains of Alzheimer's disease patients. Here, we analyzed the impact of aberrant ceramide levels on amyloid ␤-peptide (A␤) generation by using a cell-permeable analog of ceramide, C6-ceramide, and several biochemical inhibitors of the sphingomyelin/glycosphingolipid biosynthetic pathway. We found that C6-ceramide increased the biogenesis of A␤ by affecting ␤-but not ␥-cleavage of the amyloid precursor protein. Similarly to C6-ceramide, increased levels of endogenous ceramide induced by neutral sphingomyelinase treatment also promoted the biogenesis of A␤. Conversely, fumonisin B1, which inhibits the biosynthesis of endogenous ceramide, reduced A␤ production. Exogenous C6-ceramide restored both intracellular ceramide levels and A␤ generation in fumonisin B1-treated cells. These events were specific for amyloid precursor protein and were not associated with apoptotic cell death. Pulse-chase and time-course degradation experiments showed that ceramide post-translationally stabilizes the ␤-secretase BACE1. Taken together, these data indicate that the lipid second messenger ceramide, which is elevated in the brains of Alzheimer's disease patients, increases the half-life of BACE1 and thereby promotes A␤ biogenesis.Alzheimer's disease (AD) 1 affects ϳ15 million individuals worldwide. The prevalence of the disease doubles every 5 years after age 65 and approaches 50% by age 85. Because of the ongoing increase in life expectancy, the number of people affected by this disease is rapidly increasing. The major risk factor for late-onset AD is aging (1). The molecular events that mediate the effect of aging on AD are the subjects of intensive study.The main pathogenic event that occurs in all forms of AD is the abnormal accumulation of amyloid ␤-peptide (A␤) into senile (or amyloid) plaques (2). A␤ is a 39 -43-amino acid peptide proteolytically derived from the amyloid precursor protein (APP). APP is first cleaved by ␤-site APP-cleaving enzyme 1 (BACE1) at the N terminus of A␤ (␤-cleavage), producing a C-terminal fragment (␤-APP-CTF) of ϳ12 kDa, and subsequently in the transmembrane domain (␥-cleavage) by a presenilin-harboring protease complex. The two major sites of ␥-cleavage are located at positions 40 and 42 of A␤, generating A␤ 40 and A␤ 42 , respectively.The membrane lipid ceramide is the backbone of all complex sphingolipids and acts as a second messenger in many biological events. In addition, it regulates several biochemical and genetic events that occur during aging/senescence, including inhibition of phospholipase D and c-Fos-dependent signaling pathways, retinoblastoma protein dephosphorylation, arrest of the serum/growth factor-mediated activation of protein kinase C, and arrest of DNA synthesis (3, 4). Endogenous ceramide can be generated by either de novo synthesis or hydrolysis of sphingomyelin (SM) at the cell surface, the latter being the most ...

No abstract

Amyloid beta-peptide (Abeta) accumulation in specific brain regions is a pathological hallmark of Alzheimer's disease (AD). We have previously reported that a well-characterized acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, CP-113,818, inhibits Abeta production in cell-based experiments. Here, we assessed the efficacy of CP-113,818 in reducing AD-like pathology in the brains of transgenic mice expressing human APP(751) containing the London (V717I) and Swedish (K670M/N671L) mutations. Two months of treatment with CP-113,818 reduced the accumulation of amyloid plaques by 88%-99% and membrane/insoluble Abeta levels by 83%-96%, while also decreasing brain cholesteryl-esters by 86%. Additionally, soluble Abeta(42) was reduced by 34% in brain homogenates. Spatial learning was slightly improved and correlated with decreased Abeta levels. In nontransgenic littermates, CP-113,818 also reduced ectodomain shedding of endogenous APP in the brain. Our results suggest that ACAT inhibition may be effective in the prevention and treatment of AD by inhibiting generation of the Abeta peptide.

The lipid second messenger ceramide regulates the rate of beta cleavage of the Alzheimer's disease APP (amyloid precursor protein) by affecting the molecular stability of the beta secretase BACE1 (beta-site APP cleaving enzyme 1). Such an event is stimulated in the brain by the normal process of aging, and is under the control of the general aging programme mediated by the insulin-like growth factor 1 receptor. In the present study we report that BACE1 is acetylated on seven lysine residues of the N-terminal portion of the nascent protein. This process involves lysine acetylation in the lumen of the ER (endoplasmic reticulum) and is followed by deacetylation in the lumen of the Golgi apparatus, once the protein is fully mature. We also show that specific enzymatic activities acetylate (in the ER) and deacetylate (in the Golgi apparatus) the lysine residues. This process requires carrier-mediated translocation of acetyl-CoA into the ER lumen and is stimulated by ceramide. Site-directed mutagenesis indicates that lysine acetylation is necessary for nascent BACE1 to leave the ER and move ahead in the secretory pathway, and for the molecular stabilization of the protein.