PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD), defined by the presence of beta-amyloid and tau, is the most common cause of dementia worldwide. Neuropathological studies have, however, revealed that in the majority of AD cases, beta- amyloid and tau are accompanied by the presence of other abnormal proteins. One such protein is the TAR DNA binding protein of 43 kDa (TDP-43), which is present in over 60% of AD cases. It has now become apparent that TDP-43 plays an important role in the AD neurodegenerative process. As such, our team has found strong associations between the presence and burden of TDP-43 and: (1) episodic memory loss, (2) smaller hippocampal volumes at death, (3) faster rates of hippocampal atrophy 10 years prior to death, and (4) the apolipoprotein epsilon 4 genotype, all which support TDP-43 as one of the important players in AD neurodegeneration. Recently, we reported two different types of TDP-43 deposited in the brains of patients with AD that we termed TDP-43 type-? and type-?. TDP-43 type-? is similar to TDP-43 seen in the brains of patients with frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) while type-?, is different, and is associated with neurofibrillary tangles, and hence tau. What is currently lacking though is an understanding of the mechanism/s underlying TDP-43 neurodegeneration in AD. TDP-43 is an RNA-binding protein known to regulate many facets of RNA metabolism; thus, TDP-43-associated toxicity in AD may result from the accumulation of key aberrant transcripts as a result of TDP-43 mislocalization to the cytoplasm, abnormal post- translational modifications to TDP-43 and/or TDP-43 sequestration into inclusions. One of these key aberrant transcripts may be the recently discovered truncated transcript variant of a microtubule-associated protein that is involved in axonal regeneration, termed stathmin-2 (STMN2). It has been demonstrated that decreased levels of TDP-43 lead to the accumulation of a truncated variant of STMN2 that lacks exons 2 through 5 (tSTMN2). Our exciting preliminary data shows that in FTLD-TDP, tSTMN2 is significantly elevated in frontal cortex where it correlates not only with TDP-43 burden but also with age at onset, yet not with survival after onset, suggesting that increased tSTMN2 RNA accelerates disease onset but does not alter the rate of disease progression. Therefore, given similarities between TDP-43 type-? in AD and TDP-43 in FTLD-TDP could the accumulation of tSTMN2 be involved in the mechanism of TDP-43-induced neurodegeneration in AD? Furthermore, given the link between TDP-43 type-? and neurofibrillary tangles, are there other unique aberrant transcripts that are specific towards toxicity in AD and which contribute to the pathogenesis of AD? We will leverage our knowledge and experience with clinical, pathological, neuroimaging, molecular and biological aspects of TDP-43 in AD and FTLD, by assessing relationships between STMN2, TDP-43 (including type-? and type-?), and clinical and neuroimaging features in a large cohort of 756 clinically and pathologically well- characterized cases with AD neuropathologic changes.
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