IMPAIRED LEARNING AND LTP IN MICE EXPRESSING THE CARBOXY-TERMINUS OF THE ALZHEIMER AMYLOID PRECURSOR PROTEIN

Proteolytic processing of amyloid precursor protein (APP) through an e ndosomal/lysosomal pathway generates carboxyterminal polypeptides that contain an intact beta-amyloid domain(1-3). Cleavage by as-yet uniden tified proteases releases the beta-amyloid peptide in soluble form(4-6 ). In Alzheimer's disease, aggregated beta-amyloid is deposited in ext racellular neuritic plaques. Although most of the molecular mechanisms involving beta-amyloid and APP in the aetiology of Alzheimer's diseas e are still unclear, changes in APP metabolism maybe important in the pathogenesis of the disease, Here we show that transgenic mice express ing the amyloidogenic carboxy-terminal 104 amino acids of APP develop, with ageing, extracellular beta-amyloid immunoreactivity, increased g liosis and microglial reactivity, as well as cell loss in the CA1 regi on of the hippocampus. Adult transgenic mice demonstrate spatial-learn ing deficits in the Morris water maze and in maintenance of long-term potentiation (LTP). Our results indicate that alterations in the proce ssing of APP may have considerable physiological effects on synaptic p lasticity.