Genes, models and Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that is claiming an increasing number of victims as the world population ages. The identification of gene mutations and polymorphisms that either cause AD or significantly increase the risk for developing it enabled the creation of a whole generation of realistic rodent models of the disease. Animals expressing mutated human amyloid precursor protein and presenilin 1 show dramatic parallels to AD, although none of the models appear to capture the full range of pathologies that characterize the human disease. Increased refinement of these models will enhance the already tantalizing possibility of treatment.

Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein.

Specific patterns of neuronal firing induce changes in synaptic strength that may contribute to learning and memory. If the postsynaptic NMDA (N-methyl-D-aspartate) receptors are blocked, long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and the learning of spatial information are prevented. The NMDA receptor can bind a protein known as postsynaptic density-95 (PSD-95), which may regulate the localization of and/or signalling by the receptor. In mutant mice lacking PSD-95, the frequency function of NMDA-dependent LTP and LTD is shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation. In keeping with neural-network models that incorporate bidirectional learning rules, this frequency shift is accompanied by severely impaired spatial learning. Synaptic NMDA-receptor currents, subunit expression, localization and synaptic morphology are all unaffected in the mutant mice. PSD-95 thus appears to be important in coupling the NMDA receptor to pathways that control bidirectional synaptic plasticity and learning.