Increased caveolin-1 expression in Alzheimer’s disease brain
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.
References (52)
- et al.
Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein
J. Biol. Chem.
(1996) - et al.
Axonal amyloid precursor protein expressed by neurons in vitro is present in a membrane fraction with caveolae-like properties
J. Biol. Chem.
(1996) - et al.
Cholesterol and caveolae: structural and functional relationships
Biochim. Biophys. Acta
(2000) - et al.
Emerging themes in lipid rafts and caveolae
Cell
(2001) - et al.
Caveolae, plasma membrane microdomains for alpha-secretase-mediated processing of the amyloid precursor protein
J. Biol. Chem.
(1998) - et al.
Statins and the risk of dementia
Lancet
(2000) - et al.
Changes in caveolin subtype protein expression in aging rat organs
Mol. Cell Endocrinol.
(2001) - et al.
Evidence for changes in the Alzheimer’s disease brain cortical membrane structure mediated by cholesterol
Neurobiol. Aging
(1992) - et al.
Up-regulation of caveolin attenuates epidermal growth factor signaling in senescent cells
J. Biol. Chem.
(2000) - et al.
Alterations of cerebral metabolism in probable Alzheimer’s disease: a preliminary study
Neurobiol. Aging
(1994)
Apolipoprotein E polymorphism and Alzheimer’s disease
Lancet
Measurement of mRNA by quantitative PCR with a nonradioactive label
J. Lipid Res.
Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts
Curr. Biol.
Caveolin, a protein component of caveolae membrane coats
Cell
Quantitative reverse transcription-polymerase chain reaction to study mRNA decay: comparison of endpoint and real-time methods
Anal. Biochem.
A severe loss of choline acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein epsilon 4 allele
Neurosci. Lett.
Intraneuronal beta-amyloid immunoreactivity in the CNS
Neurobiol. Aging
Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro
Anal. Biochem.
Changes in lipid composition of cortical synaptosomes from different age groups of mice
Life Sci.
Lowering the cholesterol content of MA104 cells inhibits receptor-mediated transport of folate
J. Cell Biol.
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families
Science
Apolipoprotein E polymorphism and atherosclerosis
Arteriosclerosis
Abnormal cholesterol processing in Alzheimer’s disease patient’s fibroblasts
Neurobiol. Lipids
The relationship between apolipoprotein E4 and lipid metabolism is impaired in Alzheimer’s disease
Gerontology
Effects of aging and beta-amyloid on the properties of brain synaptic and mitochondrial membranes
J. Neural. Transm.
Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo
Proc. Natl. Acad. Sci. U.S.A.
Cited by (104)
SARS-CoV-2 infection increases the gene expression profile for Alzheimer's disease risk
2022, Molecular Therapy Methods and Clinical DevelopmentCaveolar and non-Caveolar Caveolin-1 in ocular homeostasis and disease
2022, Progress in Retinal and Eye ResearchTherapeutic nanotechnologies for Alzheimer's disease: A critical analysis of recent trends and findings
2022, Advanced Drug Delivery Reviews25-Hydroxycholesterol suppress IFN-γ-induced inflammation in microglia by disrupting lipid raft formation and caveolin-mediated signaling endosomes
2022, Free Radical Biology and MedicineCaveolin-1, a novel player in cognitive decline
2021, Neuroscience and Biobehavioral ReviewsSynapsin-caveolin-1 gene therapy preserves neuronal and synaptic morphology and prevents neurodegeneration in a mouse model of AD
2021, Molecular Therapy Methods and Clinical Development