Caveolin-1 in synaptic signalling and neuronal plasticity : implications for Alzheimer's disease

Increasing evidence indicates 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 homeostasis and signalling. The global working hypothesis of the present project was to investigate on a possible role for caveolin in the pathophysiological events underlying AD.More specifically, a first study was conducted to evaluate potential changes in the amount of brain caveolin in autopsy-confirmed AD and age-matched control subjects. Using rodents, the effect of age and apolipoprotein E (ApoE) deficiency on caveolin levels was also examined. In a second study, caveolin levels were investigated in an in vivo mouse paradigm of neuronal response to damage, the entorhinal cortex lesion. Moreover, the effect of caveolin on remodelling processes following neuronal lesion was examined in an in vitro model of reactive neuronal plasticity. Given the important role of caveolin in signalling, a third study was conducted to assess the potential functional interaction of caveolin with phospholipase A2 (PLA2), an enzyme implicated in synaptic plasticity and neurotransmission.The results indicated an up-regulation of caveolin in the brain of AD patients, aged mice and apoE-deficient mice, that was potentially linked to alterations of cholesterol distribution in the plasma membrane of brain cells. Consistent with this idea, caveolin levels were increased during the neuronal membrane remodelling period following entorhinal cortex lesion in mice. In vitro, caveolin overexpression in neuron-like cells undergoing post-injury reactive plasticity caused significant biochemical and morphological alterations. Finally, a co-localisation and a functional interaction of caveolin with PLA2 was observed in hippocampal neurons. This interaction dramatically inhibited PLA2 enzymatic activity and consequently interfered with synaptic AMPA glutamate receptor binding properties.These findings show that caveolin plays an important role in reactive neuronal remodelling process associated with age or damage. Its increased expression in brain cells, possibly ascribed to alterations in membrane cholesterol homeostasis, could negatively interfere with PLA2 and AMPA glutamate receptor functions during synaptic plasticity-related events. These findings are consistent with the hypothesis that part of the pathophysiology underlying AD may be related to cholesterol homeostasis, and indicate that caveolin may be an important and previously unrecognised player in this process