Alzheimer's Disease: A Challenge for BAPtists and TAUists

Alzheimer's disease (AD) is characterized clinically by a progressive loss of memory and other cognitive functions, resulting in dementia. The cognitive decline is associated with neuron loss and the accumulation in the brain of both extracellular beta-amyloid (Abeta42) containing plaques and intracellular neurofibrillary tangles (NFT). The latter contain hyperphosphorylated tau protein as the major proteinaceous component. Tau pathology is a central neuropathological characteristic of many neurodegenerative disorders that are characterized by dementia. To model tau aggregation and NFT formation in vivo, we generated transgenic mice which express human tau together with mutation P301L which is associated with FTDP-17, an inherited form of dementia with similarities to AD. To test the amyloid cascade hypothesis, that claims a role of beta-amyloid in NFT formation, we stereotaxically injected beta-amyloid into brains of transgenic and control mice. Beta-amyloid induced a five-fold increase in NFT in the amygdala of P301L transgenic mice, but not in that of control mice. NFT formation was associated with phosphorylation of tau at S422. Mutagenesis of this epitope in a human tissue culture system abrogated both the Abeta42-mediated reduction in tau solubility and tau filament formation. Amygdala-dependent tasks revealed that P301L mice had anxiety levels not different from wild-types, but their exploratory behavior was significantly increased. Acquisition of a fear response to tone and context as well as taste aversion was comparable to wild-types. However, extinction of a conditioned taste aversion (CTA) was significantly accelerated. To gain insight into pathogenic mechanisms, we used proteomic and transcriptomic approaches. Differentially expressed genes were identified with Affymetrix chips followed by real-time quantitative PCR, in situ hybridization analysis of brain sections, and Northern blots. One of the upregulated genes, glyoxalase I, is part of a cellular detoxification pathway and prevents the formation of advanced glycation end-products (AGEs). We found an accumulation of glyoxalase I protein in tangle-shaped neurons in AD brain. The proteomic approach identified proteins involved in detoxification, mitochondrial function and neurite outgrowth. Together, we aim to identify genes involved in filament formation and neurodegeneration, to dissect patho-cascades and to develop treatment strategies designed to prevent or halt AD and related disorders.