Role of apoE isoforms in AB-induced neurotoxicity in a model of basal forebrain neurons.

LUCILA SAAVEDRA; MEE-SOOK SONG; ELENA POSSE DE CHAVES

Washington DC-USA

Conferencia; Society for Neuroscience; 2005

Society for Neuroscience

Basal forebrain cholinergic neurons (BFCNs) degenerate in AD and the degree of this degeneration correlates with the degree of dementia. Early reports demonstrated that the learning and memory deficits observed in AD patients are caused at least in part by the progressive loss of BFCNs. A link between cholinergic mechanisms and the role of Ab¬ is emerging. It has been shown that the neurotoxic effects of Ab¬ appear more rapidly in the cholinergic axon terminals than in the perikarya. Interestingly, in brain of AD patients there is also a clear reduction of choline acetyl transferase (ChAT) at the hippocampus and temporal cortex. Importantly, this reduction depends on the decrease of the total number of cholinergic neurons as well as on the dosage of e4 allele of apoE, the only risk factor that has been consistently found associated with the late-onset form of AD. Several mechanisms have been proposed to explain the differential effect of apoE isoforms. An issue in debate is, whether the apoE2/apoE3 proteins protect the brain from AD or the apoE4 protein initiates the pathology. Using a three-compartmented culture system, we demonstrate that exposure of axons to Ab¬1-42 activates an independent destruction program in axons, which leads to nuclear apoptosis. Ab¬-induced axonal degeneration does not involve local caspase activation, but causes caspase activation in cell bodies. Accordingly, inhibition of caspase activation blocks Ab¬-induced apoptosis but not axonal degeneration. In agreement with previous suggestions that disruption of nerve growth factor (NGF)-mediated signaling might contribute to the loss of cholinergic neurons, we found that provision of NGF to cell bodies protects neurons from Ab¬-induced apoptosis. However, our data indicate that Ab¬-induced axonal degeneration follows a mechanism different than that activated by NGF withdrawal. Only Ab¬-induced axonal degeneration is prevented by the calpain inhibitor calpastatin and is insensitive to the inhibitor of the ubiquitin-proteasome system MG132. Importantly, inhibition of Ab¬-induced axonal degeneration by calpastatin prevents nuclear apoptosis. We next analyzed the potential uptake of Ab¬1-42 in the presence of the apoE isoforms. These results indicate that Ab¬1-42 is internalized into the distal axons and apoE4 seems to inhibit this process. Supported by Alzheimer Society of Canada, The Alzheimer Association (USA) and AHFMR (EPdeC)