Caveolin‐1 and ‐2 and their relationship to cerebral amyloid angiopathy in Alzheimer's disease

Abstract

Cerebral amyloid angiopathy (CAA) affects over 90% of patients with Alzheimer's disease (AD) and increases the risk of cerebral haemorrhage and infarction. Caveolae--cholesterol-enriched plasmalemmal microinvaginations--are implicated in the production of amyloid beta peptide (Abeta). Caveolin-1 (CAV-1) is essential for the formation of caveolae. Caveolin-2 (CAV-2) is expressed at the plasma membrane only when in a stable hetero-oligomeric complex with CAV-1. CAV-1 and CAV-2 are highly co-expressed by endothelium and smooth muscle. Recent studies suggest that down-regulation of CAV-1 causes a reduction in alpha-secretase activity and consequent accumulation of Abeta. We have used quantitative immunohistochemical techniques to assess the relationship between CAV-1 and CAV-2 with respect to Abeta accumulation in the cerebral vasculature in a series of post mortem brains. CAV-1 and CAV-2 were co-expressed within the tunica media and endothelium of cerebral blood vessels. There were regional differences in CAV-1 immunolabelling, which was significantly greater in the frontal cortex and white matter than in the parietal lobe (in both control and AD cases) or the temporal lobe (in AD alone). However, CAV-1 labelling in AD did not differ from that in controls in any of the three lobes examined. Assessment of CAV-1 labelling in relation to the severity of CAA showed CAV-1 to be significantly increased in the frontal white matter in a subgroup of AD cases with absent/mild CAA compared with controls with absent/mild CAA and to AD cases with moderate/severe CAA, but the latter groups did not show significant differences from one another. CAV-1 labelling did not vary with age, gender, APOE genotype, post mortem delay or brain weight. Only segments of blood vessels with particularly abundant Abeta and extensive loss of smooth muscle actin showed loss of CAV-1 and CAV-2 from the tunica media. Within these vessels endothelial CAV-1 was preserved and discontinuous CAV-2 labelling was noted along the outer aspect of the vessel wall. Our findings suggest that alterations in the expression of vascular CAV-1 and CAV-2 are unlikely to play a role in the development of CAA in AD.

Forced Exercise Enhances Functional Recovery after Focal Cerebral Ischemia in Spontaneously Hypertensive Rats

“…The role of caveolin-1 in the CNS [41] in the context of neuronal plasticity [18] and Alzheimer's disease [17,42] is well known, and neurological abnormalities have been reported in caveolin-1 knock-out mice [43]. Additionally, caveolin-1 has a pivotal role in cerebral ischemic injury, blocking production of NO via iNOS [23,35].…”

“…Remodeling and plasticity from cerebral ischemia require cholesterol redistribution and synthesis for the formation of new neuronal cell membrane component therefore cholesterol plays a central role in membrane compartmentalization [14,16]. Cholesterol is localized in the caveolae of cellular membranes, and caveolins bind cholesterol and transport it to injured areas [17]. These properties of caveolins suggest that they play a critical role in cell membrane remodeling and synaptic plasticity from cerebral ischemia [18].…”

MiR-124-3p attenuates hyperphosphorylation of tau protein-induced apoptosis via caveolin-1-PI3K/Akt/GSK3β pathway in N2a/APP695swe cells

“…In addition, Cav-1 was elevated in Parkin KOMEF cells, a cell model of Parkinson's disease [12]. Upregulation of Cav-1 increased alpha-secretase activity which led to increasing α -secretase-mediated cleavage of amyloid precursor protein; down-regulation of Cav-1 increased accumulation of Aβ in AD [13, 14]. Furthermore, Cav-1 has been shown as a direct target of miR-124 and miR-124-3p [3, 15] .…”

Vascular Endothelial Growth Factor Increases Permeability of the Blood–Tumor Barrier via Caveolae-Mediated Transcellular Pathway

“…The gene encoding caveolin-2 usually co-expressed with caveolin-1. Caveolin-2 combined with caveolin-1 to form heterogeneous oligomers, and is important for the formation of caveolae (Van Helmond et al 2007). In our study, the immunohistochemistry and western blot analysis revealed that the expression level of caveolae structure proteins caveolin-1 and caveolin-2 in BMECs was increased after VEGF injection, peaked at 45 min, and then decreased to the untreated level.…”