Alzheimer's Disease (AD) is now recognized as a disorder with a long incipient phase in which a myriad of pathologic abnormalities occur long before the first disease symptoms appear. The first pathologic event is the deposition of A? peptides in deposits of diffuse amyloid and in structures referred to as senile plaques. These changes may begin to occur some 20 years before the onset of symptoms. At death, individuals that exhibit only amyloid pathology are largely cognitively normal. Individuals that exhibit mild cognitive impairment at the time of death may exhibit a range of pathologic features, but a large subset show abundant amyloid pathology and some level of abnormal tau pathology (ranging from accumulation of phosphorylated tau to neurofibrillary tangles). Individuals that exhibit more severe cognitive impairment, meeting clinical criteria for diagnosis of AD, at autopsy will invariably have significant tau pathology along with amyloid (more variable in severity). This human data argues persuasively that the deposition of amyloid in some manner induces a secondary misfolding of tau. However, the inability to model the staged transition from primarily amyloid pathology to amyloid and tauopathy has impeded our ability to define the molecular mechanisms that underlie the apparent secondary induction of tau pathology in AD. To date there have been multiple attempts to produce models that replicate this important feature of AD using various transgenic and gene-targeting approaches. A key drawback to the transgenic models has been that often there is a need to express high levels of a transgene in order to raise the levels of aggregating proteins high enough that they will spontaneously seed fibrillar aggregation. With this R21, we seek to determine whether seeding amyloid pathology in mice that express much lower levels of mutant human APP and Tau will produce models in which amyloid precedes the appearance of tau pathology in a manner that is completely dependent upon the induction and severity of the amyloid pathology (as appears to occur in humans). We propose that we can generate hosts that would accomplish this goal by generating mice that co- express low levels of mutant human APP (amyloid deposition first appears at 18 months) and mutant human tau (no pathology). We hypothesize that seeded induction of amyloid deposition in mice that co-express these transgenes will create a model in which amyloid deposition in specifically accelerated, followed by a secondary induction of tau pathology. We propose that if successful, such models could be used to better understand the mechanisms that drive the transition between primarily amyloidosis to amyloid with tau pathology.
A key event in the progression of Alzheimer's disease appears to be the secondary induction of tau misfolding and aggregation that follows the early deposition of A amyloid. To date; it has not been possible to model this staged progression of pathologic changes in mice through standard transgenic modeling approaches. We seek to determine whether incorporating seeded induction of amyloidosis from human patients will produce models that faithfully replicate this critical aspect of human Alzheimer's disease.