Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Neurosciences


English (en)

Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

David Brody


Alzheimer's disease: AD) is a neurodegenerative disorder characterized pathologically by progressive neuronal loss, extracellular plaques containing the amyloid-β: Aβ) peptides, and neurofibrillary tangles: NFTs) composed of hyperphosphorylated tau proteins. Aβ is thought to act upstream of tau, affecting its phosphorylation and therefore aggregation state. One of the major risk factors for AD is traumatic brain injury: TBI). Acute intra-axonal Aβ and diffuse extracellular plaques occur in approximately 30% of human subjects following severe TBI. Intra-axonal accumulations of total and phospho-tau and less frequently NFTs have also been found in these patients. Due to the lack of an appropriate small animal model, it is not completely understood if and how these acute accumulations contribute to subsequent AD development. Furthermore, mechanisms underlying Aβ and tau pathologies post TBI have not been thoroughly investigated, nor is it known if Aβ also acts upstream of tau in this context. Here we report that controlled cortical impact TBI in 3xTg-AD mice resulted intra-axonal Aβ accumulations and increased phospho-tau immunoreactivity within hours and up to 7 days post TBI. Given these findings, we investigated the relationship between Aβ and tau pathologies following trauma in this model by systemic treatment of Compound E to inhibit γ-secrectase activity, a proteolytic process required for Aβ production. Compound E treatment successfully blocked post-traumatic Aβ accumulation in these injured mice. However, tau pathology was not affected. Furthermore, rapid intra-axonal amyloid-β accumulation was similarly observed post TBI in APP/PS1 mice, another transgenic Alzheimer's disease mouse model, and acute increases in total and phospho-tau immunoreactivity were also evident in single transgenic TauP301L mice subjected to TBI. These data provide further evidence for the causal effects of TBI on acceleration of acute Alzheimer-related abnormalities and the independent relationship between amyloid-β and tau in the setting of brain trauma. We next used the 3xTg-AD TBI model to investigate mechanisms responsible for increased tau phosphorylation post brain trauma. We found that TBI resulted in abnormal axonal accumulation of a number of kinases found to phosphorylate tau, including protein kinase A: PKA), extracellular signal-regulated kinase 1/2: ERK1/2), cyclin-dependent kinase-5: CDK5), glycogen synthase kinase-3: GSK-3), and c-jun N-terminal kinase: JNK). Notably, JNK was markedly activated in injured axons and colocalized with phospho-tau. We therefore treated mice intracerebroventricularly immediately after TBI with a peptide inhibitor of JNK, D-JNKi1, which specifically blocks interaction of JNK and its substrates. We found that moderate reduction of JNK activity: 40%) was sufficient to significantly reduce total and phospho-tau accumulations in axons of TBI mice. These data suggest targeting JNK pathway may be useful in reducing tau pathology and its adverse effects in the setting of brain trauma. Finally, we investigated whether these acute pathologies negatively contribute to long-term neurodegenerative and behavioral deficits, act as a protective response, or play a neutral role following TBI. In addition, we sought to understand the role of mutant PS1M146V in TBI-induced neurodegeneration. Overall, we found that TBI resulted in chronic axonal Aβ pathology in the absence of plaques in injured 3xTg-AD mice. TBI also caused chronic tau pathology as evidenced by PHF1 tau staining in both injured 3xTg-AD and PS1 littermate controls. Furthermore, TBI caused progressive neurodegeneration and impairments in spatial learning of injured mice, regardless of genotypes. In summary, these data demonstrate a single episode of TBI can have long lasting effects on neuronal functions and contributes to cognitive deficits, which are independent of the acute post-traumatic Aβ and tau pathologies.



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