ROLE OF HSP 110 IN TAUOPATHY

Potential Impact on Veteran's Heath care is that traumatic brain injury (TBI), which is the main cause of deathand disability in people under 35 and a common occurrence in combat situations, leads to significant deficiencyin cognitive and social problems and significant amyloid beta (A¿) generation. Furthermore, there is evidenceof increased amyloid deposition and an increased risk of development of Alzheimer's disease (AD) followingTBI. However, our knowledge regarding the treatment of AD is still incomplete. The neuropathologicalhallmarks of AD and other tauopathies include accumulation of senile plaques and/or neurofibrillary tangles(NFTs) that causes neurons to degenerate. Clinical records suggest that tau, which is localized in axons, playsa pivotal role in neurodegenerative disorders that are related to protein malfunction. Heat shock proteins(Hsps) such as Hsp110 and Hsp70i are highly expressed following exposure to environmental insults. Theirrole in neuronal disorders is supported by studies showing that several Hsps are components of NFTs. Assuch, Hsps have been detected in NFTs containing tau, in neuritic plaques of AD brain, and in the brain tissuefollowing TBI. A direct indication of the role of Hsps in neurodegenerative disease is provided by our discoverythat hsp110-/- mice exhibit an age-dependent accumulation of hyperphosphorylated tau (p-tau) andneurodegeneration. We have also found that Hsp110, tau, and Pin1 isomerase, whose deletion in mice leadsto tauopathy are in the same complexes. Since the Hsp110 family member, Hsp70 has been shown to beinvolved in amyloid precursor protein (APP) processing in cells, we tested if hsp110-/- mice crossed with miceexpressing a mutant APP (Tg2576+) exhibit accelerated pathology in vivo. Results indicate that indeed hsp110-/-Tg2576+ mice exhibit neuritic plaques at a younger age than the hsp110+/+Tg2576+ mice strongly suggesting arole for Hsp110 (and Hsp70i) in AD pathology in vivo. Therefore, understanding the mechanisms by whichHsp110 and Hsp70i prevent p-tau accumulation, reduce AD pathology, and impact TBI are the subject of thisgrant application. We hypothesize that Hsp110 and Hsp70i are critical for proper dephosphorylation of tau andare protective during AD and following TBI, and prevent neuronal death. In our proposed studies, we willdetermine the expression and intra-axonal localization of Hsp110, Hsp70i, tau, or if Hsp110 and Hsp70i aresubstrates of Pin1. As an example of neurodegenerative diseases associated with tauopathy, we will usehsp110-/-Tg2576+ mice to establish the role of Hsp110 complexes in APP processing and A¿ production in vivo;since the expression of Hsps increases following environmental insults and because TBI is known to increasethe risk for developing AD, we will investigate if the presence of Hsp110 and Hsp70i play a role in the recoveryfrom TBI, and if transiently increasing the levels of Hsps accelerate recovery following TBI; we will alsoexamine the brain tissue sections from healthy or AD patients to determine the locations of Hsp110, Hsp70i insenile plaques; Finally, we will use cerebral spinal fluid (CSF) from the patients who have received TBI todetermine whether the levels of Hsp110 or Hsp70i following injury correlates with the extent of brain injury.