All ETDs from UAB

Advisory Committee Chair

Erik D Roberson

Advisory Committee Members

David G Standaert

John J Hablitz

Scott Wilson

Lori L McMahon

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Alzheimer disease (AD) is a devastating neurological condition that slowly destroys memory and thinking skills of the affected patients. No disease-modifying medications are available. While all the treatment against Aߒ (major component of one hallmark pathology of AD) failed in clinical trials, tau (major component of the other hallmark pathology of AD) is emerging as a better alternative. Germline knockout of tau does not cause overt abnormalities in young mice and prevents AD-like deficits in mouse models of AD. Germline knockout of tau also confers resistance to epileptiform activity in models of both AD and epilepsy. Therefore tau is proposed as a drug target for AD and other conditions with epileptiform activity. However, the long-term effects of tau reduction in aged mice are controversial. The efficacy and safety of tau reduction in adulthood is unknown. To test the long-term effects of tau reduction, we comprehensively characterized a cohort of aged mice with germline knockout of tau. We demonstrated that partial tau reduction does not cause any detectable abnormality in aged mice, and complete loss of tau causes a phenotype of hyperactivity in aged mice but no motor impairment and no neurodegeneration. We also demonstrated that seizure protective effects of tau reduction persist with aging. To test the whether tau reduction in adulthood is beneficial and safe, we developed a new line of inducible knockout mice. This enables us to maintain normal level of tau expression during development and to reduce tau levels in adult mice. By characterizing those mice with adulthood tau knockout, we demonstrated that tau reduction in adulthood does not cause overt abnormalities, and that tau reduction in adulthood confers resistance to epileptiform activity in two seizure models. Overall, our findings support the long-term safety of tau reduction as well as safety and benefits of tau reduction in adulthood. Our work further validates tau as a target for Alzheimer disease and other conditions with epileptiform activity.

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