Alzheimer's disease (AD) is the most common cause of dementia in the elderly and presents a great burden to sufferers and to society. The genetics of rare Mendelian forms of AD have been central to our understanding of AD pathogenesis for the past twenty years and now the genetics of the common form of the disease in the elderly is beginning to be unravelled by genome-wide association studies. Four new genes for common AD have been revealed in the past year, CLU, CR1, PICALM and BIN1. Their possible involvement in lipid metabolism and how that relates to AD is discussed here.
"In observational studies, high serum cholesterol levels have been associated with increased risk of AD [1,2]. Genetic linkage and genome-wide association studies have identified a number of genes involved with cholesterol metabolism and transport as AD susceptibility loci [3,4] and cellular and molecular biology research has indicated a critical role for neuronal membrane phospholipids ('lipid rafts’) in modulating AD-associated pathogenesis . However, in animal models, apolipoprotein E modulates the relationship between low-density lipoproteins and amyloid-β (Aβ) deposition [6,7] suggesting an indirect effect of intra-cranial cholesterol on Alzheimer’s pathology. "
[Show abstract][Hide abstract] ABSTRACT: Epidemiological and molecular findings suggest a relationship between Alzheimer's disease (AD) and dyslipidemia, although the nature of this association is not well understood.
Using linear mixed effects models, we investigated the relationship between CSF levels of heart fatty acid binding protein (HFABP), a lipid binding protein involved with fatty acid metabolism and lipid transport, amyloid-beta (Abeta), phospho-tau, and longitudinal MRI-based measures of brain atrophy among 295 non-demented and demented older individuals. Across all participants, we found a significant association of CSF HFABP with longitudinal atrophy of the entorhinal cortex and other AD-vulnerable neuroanatomic regions. However, we found that the relationship between CSF HABP and brain atrophy was significant only among those with low CSF Abeta1--42 and occurred irrespective of phospho-tau181p status.
Our findings indicate that Abeta-associated volume loss occurs in the presence of elevated HFABP irrespective of phospho-tau. This implicates a potentially important role for fatty acid binding proteins in Alzheimer's disease neurodegeneration.
[Show abstract][Hide abstract] ABSTRACT: Perturbation of lipid metabolism favours progression of Alzheimer disease, in which processing of Amyloid Precursor Protein (APP) has important implications. APP cleavage is tightly regulated by cholesterol and APP fragments regulate lipid homeostasis. Here, we investigated whether up or down regulation of full-length APP expression affected neuronal lipid metabolism. Expression of APP decreased HMG-CoA reductase (HMGCR)-mediated cholesterol biosynthesis and SREBP mRNA levels, while its down regulation had opposite effects. APP and SREBP1 co-immunoprecipitated and co-localized in the Golgi. This interaction prevented Site-2 protease-mediated processing of SREBP1, leading to inhibition of transcription of its target genes. A GXXXG motif in APP sequence was critical for regulation of HMGCR expression. In astrocytes, APP and SREBP1 did not interact nor did APP affect cholesterol biosynthesis. Neuronal expression of APP decreased both HMGCR and cholesterol 24-hydroxylase mRNA levels and consequently cholesterol turnover, leading to inhibition of neuronal activity, which was rescued by geranylgeraniol, generated in the mevalonate pathway, in both APP expressing and mevastatin treated neurons. We conclude that APP controls cholesterol turnover needed for neuronal activity.
EMBO Molecular Medicine 04/2013; 5(4):608-25. DOI:10.1002/emmm.201202215 · 8.67 Impact Factor
"Alzheimer's disease (AD) is the most common form of dementia with a prevalence of ∼1% in western populations at the age of 65, rising to 25–35% in those over 85 (1). While AD is genetically complex, it is also highly heritable, with recent estimates of heritability ranging from 58 to 79% (1). Neuropathologically, the disease is characterized by extracellular senile plaques containing β-amyloid (Aβ), intracellular neurofibrillary tangles containing hyperphosphorylated tau protein and loss of synapses (2). "
[Show abstract][Hide abstract] ABSTRACT: We assessed the role of rare copy number variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlapping APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between SNPs and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbor significantly fewer deletions >1Mb than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 x 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and ADHD, CNVs do not appear to make a significant contribution to the development of AD.
Human Molecular Genetics 11/2012; 22(4). DOI:10.1093/hmg/dds476 · 6.39 Impact Factor
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