Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder believed to be initiated by accumulation of amyloid β (Aβ)-related peptides derived from proteolytic processing of amyloid precursor protein (APP). Research over the past two decades provided a mechanistic link between cholesterol and AD pathogenesis. Genetic polymorphisms in genes regulating the pivotal points in cholesterol metabolism have been suggested to enhance the risk of developing AD. Altered neuronal membrane cholesterol level and/or subcellular distribution have been implicated in aberrant formation, aggregation, toxicity, and degradation of Aβ-related peptides. However, the results are somewhat contradictory and we still do not have a complete understanding on how cholesterol can influence AD pathogenesis. In this review, we summarize our current understanding on the role of cholesterol in regulating the production/function of Aβ-related peptides and also examine the therapeutic potential of regulating cholesterol homeostasis in the treatment of AD pathology.

Analyses of frequency profiles of markers on disease or drug-response related genes in diverse populations are important for the dissection of common diseases. We report the results of analyses of data on 405 SNPs from 75 such genes and a 5.2 Mb chromosome, 22 genomic region in 1871 individuals from diverse 55 endogamous Indian populations. These include 32 large (>10 million individuals) and 23 isolated populations, representing a large fraction of the people of India. We observe high levels of genetic divergence between groups of populations that cluster largely on the basis of ethnicity and language. Indian populations not only overlap with the diversity of HapMap populations, but also contain population groups that are genetically distinct. These data and results are useful for addressing stratification and study design issues in complex traits especially for heterogeneous populations.

Niemann-Pick type C (NPC) disease, an autosomal recessive disorder caused primarily by loss-of-function mutations in NPC1 gene, is characterized neuropathologically by intracellular cholesterol accumulation, gliosis and neuronal loss in selected brain regions. Recent studies have shown that NPC disease exhibits intriguing parallels with Alzheimer's disease (AD), including the presence of tau-positive neurofibrillary tangles (NFTs) and β-amyloid (Aβ)-related peptides in vulnerable brain regions. Since enhanced cholesterol level, which acts as a risk factor for AD, can increase Aβ production by regulating amyloid precursor protein (APP) metabolism, it is possible that APP overexpression can influence cholesterol-regulated NPC pathology. We have addressed this issue in a novel bigenic mice (ANPC) generated by crossing heterozygous Npc1-deficient mice with mutant human APP transgenic mice. These mice exhibited decreased lifespan, early object memory and motor impairments, and exacerbated glial pathology compared with other littermates. Neurodegeneration observed in the cerebellum of ANPC mice was found to be accelerated along with a selective increase in the phosphorylation/cleavage of tau protein. Additionally, enhanced levels/activity of cytosolic cathepsin D together with cytochrome c and Bcl-2-associated X protein suggest a role for the lysosomal enzyme in the caspase-induced degeneration of neurons in ANPC mice. The reversal of cholesterol accretion by 2-hydroxypropyl-β-cyclodextrin (2-HPC) treatment increased longevity and attenuated behavioral/pathological abnormalities in ANPC mice. Collectively, our results reveal that overexpression of APP in Npc1-deficient mice can negatively influence longevity and a wide spectrum of behavioral/neuropathological abnormalities, thus raising the possibility that APP and NPC1 may interact functionally to regulate the development of AD and NPC pathologies.

Niemann-Pick type C (NPC) disease is an autosomal recessive neurodegenerative disorder characterized by intracellular accumulation of cholesterol and glycosphingolipids in many tissues including the brain. The disease is caused by mutations of either NPC1 or NPC2 gene and is accompanied by a severe loss of neurons in the cerebellum, but not in the hippocampus. NPC pathology exhibits some similarities with Alzheimer’s disease, including increased levels of amyloid β (Aβ)-related peptides in vulnerable brain regions, but very little is known about the expression of amyloid precursor protein (APP) or APP secretases in NPC disease. In the present study, we evaluated age-related alterations in the level/distribution of APP and its processing enzymes, β- and γ-secretases, in the hippocampus and cerebellum of Npc1−/− mice, a well-established model of NPC pathology. Our results show that levels and expression of APP and β-secretase are elevated in the cerebellum prior to changes in the hippocampus, whereas γ-secretase components are enhanced in both brain regions at the same time in Npc1−/− mice. Interestingly, a subset of reactive astrocytes in Npc1−/− mouse brains expresses high levels of APP as well as β- and γ-secretase components. Additionally, the activity of β-secretase is enhanced in both the hippocampus and cerebellum of Npc1−/− mice at all ages, while the level of C-terminal APP fragments is increased in the cerebellum of 10-week-old Npc1−/− mice. These results, taken together, suggest that increased level and processing of APP may be associated with the development of pathology and/or degenerative events observed in Npc1−/− mouse brains.

Amyloid-β (Aβ) peptides originating from β-amyloid precursor protein (APP) are critical in Alzheimer's disease (AD). Cellular cholesterol levels/distribution can regulate production and clearance of Aβ peptides, albeit with contradictory outcomes. To better understand the relationship between cholesterol homeostasis and APP/Aβ metabolism, we have recently generated a bigenic ANPC mouse line overexpressing mutant human APP in the absence of Niemann-Pick type C-1 protein required for intracellular cholesterol transport. Using this unique bigenic ANPC mice and complementary stable N2a cells, we have examined the functional consequences of cellular cholesterol sequestration in the endosomal-lysosomal system, a major site of Aβ production, on APP/Aβ metabolism and its relation to neuronal viability. Levels of APP C-terminal fragments (α-CTF/β-CTF) and Aβ peptides, but not APP mRNA/protein or soluble APPα/APPβ, were increased in ANPC mouse brains and N2a-ANPC cells. These changes were accompanied by reduced clearance of peptides and an increased level/activity of γ-secretase, suggesting that accumulation of APP-CTFs is due to decreased turnover, whereas increased Aβ levels may result from a combination of increased production and decreased turnover. APP-CTFs and Aβ peptides were localized primarily in early-/late-endosomes and to some extent in lysosomes/autophagosomes. Cholesterol sequestration impaired endocytic-autophagic-lysosomal, but not proteasomal, clearance of APP-CTFs/Aβ peptides. Moreover, markers of oxidative stress were increased in vulnerable brain regions of ANPC mice and enhanced β-CTF/Aβ levels increased susceptibility of N2a-ANPC cells to H2O2-induced toxicity. Collectively, our results show that cellular cholesterol sequestration plays a key role in APP/Aβ metabolism and increasing neuronal vulnerability to oxidative stress in AD-related pathology.