5.Tau Transgenic Mouse Models in Therapeutic Development医学电子书.pdfVIP

Neuronal Cytoskeleton and the Tau Hypothesis Tau Transgenic Mouse Models in Therapeutic Development Hanno M. Roder Abstract Although a unifying animal model of Alzheimer’s disease (AD) has not been forthcoming, specific pathological features have been successfully induced in transgenic mice with mutated human genes identified by genetic analysis. A particular problem is that the defining pathologies of AD, amyloid-b peptide amyloidosis, and neurofibrillary tangles formed by the abnormally modified microtubule-associated protein tau cannot both be induced by a single mutation as in humans, calling in question straightforward cause–effect hypotheses. On the contrary, the separate manifestation of these pathologies in mice points to their distinct functional consequences: amyloid-b pathology interferes with synaptic efficiency but does not by itself drive neurodegeneration, while tau pathology appears to be the direct mechanism of neuronal degeneration and brain atrophy. In both cases, however, the latest data favor a dominant role of biochemical precursors to the obvious neuropathological structures, which originally defined the disease. In any case, for therapeutic development, tau pathology needs to be addressed for lasting treatment results in AD. Initial therapeutic studies with mouse models of tauopathy support their utility in the discovery of antineurodegenerative therapeutic principles. Moreover, certain aspects of tau pathology and their functional conse- quences may be partially reversible. Apart from such immediate utility, transgenic mouse models also promise to provide unique insights into the biochemical details of tau pathology, which are impossible to obtain from human AD brains. 1 Challenges to Modeling Alzheimer’s Disease The understanding of the molecular path