This R21 application proposes to develop and characterize a new model for Alzheimer disease (AD) research. In patients with AD, the earliest neuronal lesions occur primarily in the entorhinal cortex. Thereafter a hierarchical march of lesions involves limbic and association areas. Destruction of the perforant pathway, the entorhinal cortex projection to the dentate gyrus, is known to deafferent the hippocampus in AD. As the disease progresses, disruption of these pathways and closely related structures in the medial temporal lobe are believed to explain why memory impairments so dominate the clinical symptoms of AD. We have established a transgenic model in which P301L tau overexpression is limited to the same set of stellate neurons most vulnerable for tangle formation in AD, layer II of the entorhinal cortex, utilizing an established tet response promoter known to have specificity for these neurons and a tauP301L responder. This line, referred to as rTauP301L EC, expresses tau robustly in the EC. This leads to early (by 3 months of age) localization of misfolded tau in the perforant pathway and its terminals in the dentate gyrus terminal zone. Over the next 18 months, synaptic loss occurs, a robust neuroplasticity phenomenon with sprouting of AChE positive fibers into the deafferented zone occurs, tangles form, and (months later) neuronal loss ensues. Intriguingly, in animals ~18 months of age, neurons anatomically connected to the EC, but which do not express the transgene, develop tau positive inclusions, presumably from misfolded endogenous tau and/or from translocation across synapses of misfolded tau protein. A second line is proposed as well, utilizing a newly generated wild type tau responder line (rTg21221) that is entirely comparable to the rTauP301L EC line but lacks the mutation. We propose to characterize these models in terms of plasticity phenomenon, determine whether suppressing the transgene at various points can prevent ongoing degeneration, and determine whether the animals develop a behavioral phenotype of memory impairments in order to establish a model of the early changes of AD and of progressive pathology. We believe that it is critical to establish models of early disease processes to both understand the pathophysiology of progression and to generate a system in which to test neuroprotective therapies - a first step in designing interventions at a """"""""presymptomatic"""""""" time point where they might be most effective from a clinical perspective.
Alzheimer disease starts with neurofibrillary lesions in a special brain area, the entorhinal cortex, which is responsible for memory related brain functions. We propose to make a model of this stage of the disease by genetically engineering a mouse to develop these same lesions in only this brain area;doing so will allow us to study the earliest phase of the disease, and to learn about whether early lesions lead to disease progression.
|Polydoro, Manuela; Dzhala, Volodymyr I; Pooler, Amy M et al. (2014) Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer's disease model. Acta Neuropathol 127:257-70|
|Pooler, Amy M; Polydoro, Manuela; Wegmann, Susanne K et al. (2013) Tau-amyloid interactions in the rTgTauEC model of early Alzheimer's disease suggest amyloid-induced disruption of axonal projections and exacerbated axonal pathology. J Comp Neurol 521:4236-48|
|de Calignon, Alix; Polydoro, Manuela; Suárez-Calvet, Marc et al. (2012) Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73:685-97|
|Walker, Lary C; Diamond, Marc I; Duff, Karen E et al. (2012) Mechanisms of Protein Seeding in Neurodegenerative Diseases. Arch Neurol :1-7|