Elsevier

Neurobiology of Aging

Volume 25, Issue 6, July 2004, Pages 753-759
Neurobiology of Aging

Increased caveolin-1 expression in Alzheimer’s disease brain

https://doi.org/10.1016/j.neurobiolaging.2003.07.004Get rights and content

Abstract

Increasing evidence suggests that cholesterol plays a central role in the pathophysiology of Alzheimer’s disease (AD). Caveolin is a cholesterol-binding membrane protein involved in cellular cholesterol transport. We investigated the changes in the protein amount of hippocampal caveolin of autopsy-confirmed AD and aged-matched control subjects. Our results demonstrate that caveolin protein levels in the hippocampus and caveolin mRNA in the frontal cortex are up-regulated in AD by approximately two-fold, compared to control brains. These results suggest a relationship between caveolin-1 expression levels and a dysregulation of cholesterol homeostasis at the plasma membrane of brain cells. In support of this hypothesis, a significant increase in caveolin protein levels has also been observed in hippocampal tissue from ApoE-deficient (knockout) and aged wild-type mice; two situations associated with modifications of transbilayer distribution of cholesterol in brain synaptic plasma membranes. These results indicate that caveolin over-expression is linked to alterations of cholesterol distribution in the plasma membrane of brain cells and are consistent with the notion of a deterioration of cholesterol homeostasis in AD.

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by alterations of cholesterol homeostasis in both the periphery and the central nervous system. Alterations in cholesterol distribution have been shown to be closely associated with the presence of the apoε4 allele of the Apolipoprotein E (ApoE) in AD and control subjects [5], [7]. The apoε4 allele (as opposed to the ε2 and ε3 alleles) is a well-known risk factor for sporadic and familial late onset AD [4], [34], [48]. Patients with two ε4 alleles exhibit an earlier age of onset [4], [38], higher amyloid levels and amyloid plaque counts [13], [42], cerebrovascular amyloid [37] and a marked reduction in choline acetyltransferase [34], [46] compared to non-ε4 allele AD subjects.

Further substantiating the link between cholesterol homeostasis and AD, recent observations from epidemiological studies have shown that the use of cholesterol-lowering agents, like Probucol or statins, reduce the prevalence of AD [17], [51] and affect amyloid production and cognitive deterioration [35], [40]. Although the protective mechanism of cholesterol-lowering drugs remains largely unknown, it is postulated that alterations in brain cholesterol homeostasis could explain both the reduced risk and the alteration in beta amyloid metabolism observed in AD [9], [45], [47].

Cholesterol plays an important role in cellular function and membrane compartmentalization. It is an essential component of lipid rafts, dense lateral assemblies of cholesterol, and sphingolipids in the exoplasmic leaflet of the plasma membrane bilayer [44]. Caveolae, which are considered to be a specific form of raft, are omega-shaped membrane invaginations involved in cell signaling, transcytosis, and in the regulation of cellular cholesterol homeostasis [10], [12].

Caveolin, a 21–24 kDa integral membrane protein, is a principal component of caveolae membranes in vivo [21], [41]. Both the formation of caveolae at the cell surface and caveolin expression are modulated by the cholesterol content of the cell. Increases in cellular cholesterol levels up-regulate caveolin expression, while cholesterol depletion suppresses caveolin production [10]. There is increasing appreciation of the role of caveolin as a key sensor and modulator of membrane cholesterol levels, and several recent observations connect caveolin to signal transduction via cholesterol regulation. A good example of this is the emerging role of caveolin and cholesterol in the proteolytic processing of amyloid precursor protein (APP). The generation of amyloid beta (Aβ), the amyloidogenic peptide of APP, has been associated with membrane regions of high cholesterol content, such as lipid rafts or caveolae [1], [20], [22], [45]. In contrast, sites of APPsα production in the non-amyloidogenic pathway, occur in membrane regions with low cholesterol content and high fluidity [20]. Caveolin-1 has been shown to physically associate with APP [15], which further supports the idea that caveolae and caveolin may play a pivotal role in the proteolysis of APP in vivo.

The aim of the present study was to determine the expression of caveolin-1 in the hippocampus of autopsy-confirmed AD patients as a function of disease status and ApoE genotype. We hypothesize that variations in caveolin-1 levels could be linked to modifications in membrane cholesterol distribution. Therefore, we also examined the extreme situation of a complete absence of ApoE (ApoE knockout) and the effect of age, two conditions in which membrane cholesterol distribution is affected, on caveolin expression.

Section snippets

Brain tissues and ApoE genotyping

Human hippocampal tissues from 19 autopsy-confirmed cases of AD and 16 age-matched control individuals were obtained from the Douglas Hospital Brain Bank in Montreal, Canada (Table 1). The mean age at death was 77.6±1.6 years in the AD patients and 72.4±1.2 years in the control group and did not differ significantly. Post-mortem intervals were 32.5±5.3 h in the AD patients and 33.6±4.3 h in the control group, which is not significantly different. Human frontal cortex and cerebellar tissues from

Caveolin expression in Alzheimer’s disease

Western blot analyses carried out on hippocampus extracts from AD patients and control cases showed a major reactive band with an approximate molecular mass of 20 kDa corresponding to caveolin-1 (Fig. 1A). Densitometric analysis of the caveolin-1 bands showed a statistically significant change between the two groups, the relative optic density being increased by about 100% in the AD patients hippocampal samples (P<0.005) (Fig. 1B). The caveolin-1 protein level in frontal cortex samples was also

Discussion

In the present study, we confirm the presence of caveolin-1 in both human and mouse brain. Moreover, our current data show that brain tissues from AD patients contain increased levels of caveolin-1 protein and mRNA relative to age-matched control subjects, suggesting that the cellular membrane distribution of cholesterol is altered in AD. In support of this assumption, an up-regulation in caveolin-1 protein levels has also been observed in brain tissue from ApoE knockout and aged wild-type

Acknowledgements

This work was supported by the Canadian Institute for Health Research (J.P.), the Natural Sciences and Engineering Research Council (S.B.G), Fonds de la Recherche en Santé du Québec (S.B.G.), and Alzheimer Society of Canada (S.B.G. and J.P.). We wish to thank Catherine Bélanger for critical reading of this manuscript.

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