As estimates predict that AD is likely to become one of the most important global public health issues by 2050, the urgency to develop mechanism-based disease modifying therapies for AD is ever increasing. Over the past two decades, animal model systems have been instrumental in clarifying the molecular mechanisms and testing therapeutic strategies for AD. Notwithstanding advances made using current rodent models that exhibit robust A amyloidosis and tau pathology, success in translating preclinical drug discoveries to the clinic remains rather disappointing. A major limitation of current mouse models is the lack of robust age-dependent neuronal loss induced by the interaction of amyloid and tau aggregates in their brains, salient neuropathological hallmarks of individuals with AD. To overcome this problem, we propose to characterize a recently created mouse model that not only exhibits A amyloidosis and tauopathy, but also displays robust age-dependent neuronal loss. We will use our new mouse model to test our overarching hypothesis that A? induces tau aggregation to initiate synaptic dysfunction and promote neuronal loss. We believe that such a model system will provide the opportunity for the first time to evaluate A? amyloidosis and tauopathy dependent loss of neurons as the principal outcome measure in preclinical testing of mechanism-based therapies, such as those designed to target tauopathy and/or A amyloidosis. Toward this goal, we recently generated lines of transgenic mice expressing human four-repeat tau fragment containing the ?K280 mutation (Tau-4R?K280) in the forebrain that not only developed AD-like tau aggregates but displayed memory deficits, age-dependent neuronal loss and brain atrophy. By crossbreeding Tau4R-?K280 mice with a model of A amyloidosis, APPswe;PS1?E9 mice, we generated mice that develop both Ab and tau pathologies (Tau608-AP mice). Significantly, both the tauopathy and cell death observed in Tau4R-?K280 mice were greatly accelerated in Tau608-AP mice, which support a model that the presence of A could accelerate the development of AD-like tau pathologies and age-dependent neuronal loss. Our proposal thus will allow us to focus attention on several important questions. First, it is not completely clear how accumulation of tau aggregations leads to neuronal loss. Second, it is not known whether and how A interacts with tau aggregates to promote the early pathological alterations that leads to synaptic dysfunction and accelerates neuronal loss. Finally, it remains an open question as to whether early interventions designed to target tau will attenuate neuronal loss in the presence of amyloid pathology in AD. In Project 2, we will use our novel mouse models to directly address these important questions. Our proposed studies will identify the mechanisms underlying the interactions between tau and A pathology, and provide valuable information to evaluate the effectiveness of targeting tau pathologies.
In this project, we propose to characterize a recently created mouse model that not only exhibits A amyloidosis and tauopathy, but also displays robust age-dependent neuronal loss, a key feature of AD. We will use our new mouse model to test our overarching hypothesis that A induces tau aggregation to initiate synaptic dysfunction and promote neuronal loss. More importantly, our novel model system will allow us to validate tau as a promising target as an early intervention strategy to attenuate neuronal loss in AD.
|Habes, Mohamad; Sotiras, Aristeidis; Erus, Guray et al. (2018) White matter lesions: Spatial heterogeneity, links to risk factors, cognition, genetics, and atrophy. Neurology 91:e964-e975|
|Davis, Jeremy J (2018) Performance validity in older adults: Observed versus predicted false positive rates in relation to number of tests administered. J Clin Exp Neuropsychol 40:1013-1021|
|Behrens, Stephanie; Rattinger, Gail B; Schwartz, Sarah et al. (2018) Use of FDA approved medications for Alzheimer's disease in mild dementia is associated with reduced informal costs of care. Int Psychogeriatr 30:1499-1507|
|Hanfelt, John J; Peng, Limin; Goldstein, Felicia C et al. (2018) Latent classes of mild cognitive impairment are associated with clinical outcomes and neuropathology: Analysis of data from the National Alzheimer's Coordinating Center. Neurobiol Dis 117:62-71|
|Lin, Ming; Gong, Pinghua; Yang, Tao et al. (2018) Big Data Analytical Approaches to the NACC Dataset: Aiding Preclinical Trial Enrichment. Alzheimer Dis Assoc Disord 32:18-27|
|Peng, Shin-Lei; Chen, Xi; Li, Yang et al. (2018) Age-related changes in cerebrovascular reactivity and their relationship to cognition: A four-year longitudinal study. Neuroimage 174:257-262|
|Xiong, Yulan; Neifert, Stewart; Karuppagounder, Senthilkumar S et al. (2018) Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice. Proc Natl Acad Sci U S A 115:1635-1640|
|Nicolas, Aude (see original citation for additional authors) (2018) Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron 97:1268-1283.e6|
|Bouhrara, Mustapha; Reiter, David A; Bergeron, Christopher M et al. (2018) Evidence of demyelination in mild cognitive impairment and dementia using a direct and specific magnetic resonance imaging measure of myelin content. Alzheimers Dement 14:998-1004|
|Kirson, Noam Y; Scott Andrews, J; Desai, Urvi et al. (2018) Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. J Alzheimers Dis 61:295-307|
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