Next generation humanized mice to investigate how Traumatic Brain Injury interacts with ApoE4 genetic risk factor to accelerate dementia

Abstract

AbstractBackgroundTraumatic brain injury (TBI) is among the leading causes of disability and has been strongly linked to Alzheimer’s disease (AD), the most prevalent cause of dementia. Patients with a history of repeated TBI can present pathologies and symptoms similar to AD: Tau protein neurofibrillary tangles, Amyloid Beta Plaques, and chronic inflammation. We propose that TBI triggers pathological processes that underlie AD development and thereby accelerates AD’s development and severity.Apolipoprotein E4 (ApoE4) protein has been thought to play a central role in several processes underlying AD development. ApoE4 is one of the biggest genetic risk factors for AD, which is also linked to worse short‐term and long‐term outcomes after TBI. However, how ApoE4 mechanistically affects the development of AD‐pathology after TBI has yet to be understoodMethodTo explore this gap, we will use mice with humanized genes which develop AD like pathology with age (Late‐onset AD). The humanized genes include amyloid precursor protein (hAPP) and microtubule‐associated protein tau (hMAPT) ‐ precursors to amyloid beta plaques and neurofibrillary tangles, respectively ‐ in addition to two copies of apolipoprotein E4 (ApoE4) or the control ApoE3 allele. Half of these mice will experience three mild TBIs modeled after human concussions, while the other half will only be anesthetized. All mice will undergo behavioral testing to measure cognitive deficits and molecular analyses to characterize the timing and severity of AD pathology. Cognitive testing will be carried out using the rodent touchscreen Continuous Performance Test (rCPT), which are widely used with AD patients to test attentional processes.ResultPreliminary results from rCPT before TBI, reveal no significant differences between genotypes and sex at 6‐month of age.ConclusionWe aim to uncover how TBI interacts with ApoE4 protein to accelerate AD pathology at the molecular and behavioral levels. To maximize the clinical relevance of this project, we use mice with human genes implicated in AD, a clinically relevant noninvasive model of concussion, and touchscreen cognitive testing identical to touchscreen testing in humans. We aim to bridge the gap between animal models and clinical settings to identify future therapeutic targets for TBI and AD.