Mild Traumatic Brain Injury and Early Onset Dementia Mouse Models and Disease Modifying Therapies

Recent reports have linked traumatic brain injury (TBI) ranging from sports athlete’s concussions to soldier blast impacts to earlier onset dementia. However, the link between mild trauma and its role in the ability to deplete a person’s “cognitive reserve” as they age leading to dementia is still unknown. Any advances in early identification tools, understanding sequela mechanism, and therapies for TBI would have significant socioeconomic and health care implications. To address this, we have developed an oxidative stress induced mouse model (Aldh2-/-), demonstrating aging-like pathology, in conjunction with a closed head weight drop injury model to mimic cognitive deficits and neuroinflammatory pathology that occurs post mild TBI. Our primary objective is to identify functional damage and future consequences induced by mTBI that contribute to increased risk of dementia. In the Aldh2-/- mice where oxidative stress (OS) represents a “1st hit”, Aldh2-/- mice exhibited increased levels of OS and accelerated cognitive deficits as early as 3 months. We further characterized this model using a chemoproteomic approach to identify a network of differentially expressed proteins linked to accelerated cognitive decline. More interestingly, when a “2nd hit” was administered such as mTBI, it led to an exacerbation of neuroinflammatory surge and post concussive syndrome 24 hrs post injury and sustained deficits in behavior up to 1 month. To utilize this model, we tested a novel library of small molecules that reactivate CREB through NO/cGMP signaling that have been previously evaluated for its anti-inflammatory, anti-convulsant, and pro-cognitive properties. Our results demonstrated a reversal of post-concussive syndrome, decrease in inflammation, and additional alleviated damage from other contributors of mTBI. This novel model of mTBI on a background strain of aging (Aldh2-/-) allows us to develop a preclinical model where disease modifying strategies for TBI can be tested

Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer’s Disease and Type 2 Diabetes

Selective liver X receptor (LXR) agonists have been extensively pursued as therapeutics for Alzheimer's disease and related dementia (ADRD) and, for comorbidities such as type 2 diabetes (T2D) and cerebrovascular disease (CVD), disorders with underlying impaired insulin signaling, glucose metabolism, and cholesterol mobilization. The failure of the LXR-focused approach led us to pursue a novel strategy to discover nonlipogenic ATP-binding cassette transporter A1 (ABCA1) inducers (NLAIs): screening for ABCA1-luciferase activation in astrocytoma cells and counterscreening against lipogenic gene upregulation in hepatocarcinoma cells. Beneficial effects of LXRβ agonists mediated by ABCA1 include the following: control of cholesterol and phospholipid efflux to lipid-poor apolipoproteins forming beneficial peripheral HDL and HDL-like particles in the brain and attenuation of inflammation. While rare, ABCA1 variants reduce plasma HDL and correlate with an increased risk of ADRD and CVD. In secondary assays, NLAI hits enhanced cholesterol mobilization and positively impacted in vitro biomarkers associated with insulin signaling, inflammatory response, and biogenic properties. In vivo target engagement was demonstrated after oral administration of NLAIs in (i) mice fed a high-fat diet, a model for obesity-linked T2D, (ii) mice administered LPS, and (iii) mice with accelerated oxidative stress. The lack of adverse effects on lipogenesis and positive effects on multiple biomarkers associated with T2D and ADRD supports this novel phenotypic approach to NLAIs as a platform for T2D and ADRD drug discovery

Interaction of oxidative stress and neurotrauma in ALDH2−/− mice causes significant and persistent behavioral and pro-inflammatory effects in a tractable model of mild traumatic brain injury

Oxidative stress induced by lipid peroxidation products (LPP) accompanies aging and has been hypothesized to exacerbate the secondary cascade in traumatic brain injury (TBI). Increased oxidative stress is a contributor to loss of neural reserve that defines the ability to maintain healthy cognitive function despite the accumulation of neuropathology. ALDH2-/- mice are unable to clear aldehyde LPP by mitochondrial aldehyde dehydrogenase-2 (Aldh2) detoxification and provide a model to study mild TBI (mTBI), therapeutic interventions, and underlying mechanisms. The ALDH2-/- mouse model presents with elevated LPP-mediated protein modification, lowered levels of PSD-95, PGC1-α, and SOD-1, and mild cognitive deficits from 4 months of age. LPP scavengers are neuroprotective in vitro and in ALDH2-/- mice restore cognitive performance. A single-hit, closed skull mTBI failed to elicit significant effects in WT mice; however, ALDH2-/- mice showed a significant inflammatory cytokine surge in the ipsilateral hemisphere 24 h post-mTBI, and increased GFAP cleavage, a biomarker for TBI. Known neuroprotective agents, were able to reverse the effects of mTBI. This new preclinical model of mTBI, incorporating significant perturbations in behavior, inflammation, and clinically relevant biomarkers, allows mechanistic study of the interaction of LPP and neurotrauma in loss of neural reserve