1. Departments of^*, Neurology & Neurosurgery,^§,  Psychology, ^¶,  Psychiatry, ^† McGill Centre for Studies in Aging, McGill University, Montreal, Quebec H3A 2B4, Canada
2. ^‡ Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada
3. Université du Québec à Trois-Rivières, Trois-Rivières, Quebec G9A 5H7, Canada
4. ^£Centre for Neurosdence, Montreal General Hospital, Montreal, Quebec H3G 1A4, Canada

Abstract

Proteolytic processing of amyloid precursor protein (APP) through an endosomal/lysosomal pathway generates carboxy-terminal polypeptides that contain an intact -amyloid domain^1–3. Cleavage by as-yet unidentified proteases releases the -amyloid pep tide in soluble form^4–6. In Alzheimer's disease, aggregated -amyloid is deposited in extracellular neuritic plaques.Although most of the molecular mechanisms involving-amyloid and APP in the aetiology of Alzheimer's disease are still unclear, changes in APP metabolism maybe important in the pathogenesis of the disease. Here we show that transgenic mice expressing the amyloidogenic carboxy-terminal 104 amino acids of APP develop, with ageing, extracellular -amyloid immunoreactivity, increased gliosis and microglial reactivity, as well as cell loss hi the CA1 region of the hippocampus. Adult transgenic mice demonstrate spatial-learning deficits in the Morris water maze and in maintenance of long-term potentiation (LTP). Our results indicate that alterations in the processing of APP may have considerable physiological effects on synaptic plasticity.