PROJECT SUMMARY Evidence in humans suggests that vascular risk factors, such as stroke, increase the risk of, or in some cases have a synergistic effect on, the development of Alzheimer's disease (AD). Most vascular dementia (VaD) and AD mixed dementia patients exhibit more varied pathology with respect to β-amyloid (Aβ) accumulation, brain atrophy, and neurodegeneration than typical “pure” AD patients. At present, the precise number of patients presently diagnosed with a particular type of dementia that actually have mixed dementia is not known; however, post-mortem analyses suggest that the condition may be present in over half of patients clinically diagnosed with AD. Furthermore, despite the frequent co-existence of VaD and AD, little is known about how these diseases influence each other, in part due to the lack of adequate animal models. In light of this gap, the objective of Aim 1 of this proposal is to further develop two innovative new models of mixed dementia that can be used to investigate how the long-lasting pathological sequelae of ischemic stroke impact the AD phenotype. To that end, our preliminary data show in a mixed dementia model using aged wildtype (wt) mice, impaired motor recovery and accelerated onset of cognitive impairment in aged C57BL/6 mice compared to young adult mice in the months following ischemic stroke. This behavioral manifestation corresponds with increased brain atrophy and cholinergic degeneration as well as a focal increase in Aβ and tau pathology in areas of axonal degeneration and white matter tracts of the ipsilateral hemisphere. In contrast, our preliminary data show that in a mixed dementia model using aged transgenic Aβ precursor protein transgenic mice (AβPPL/S), that ischemia exacerbates behavioral deficits and that this correlates with a global increase in Aβ and tau pathology compared to AβPPL/S mice that undergo a sham procedure. Furthermore, in both models, the stroke-induced AD pathology co-localized with the presence of, or increases in, β-secretase (BACE) 1 and neuregulin (NRG) 1 type III, both of which are necessary for myelin repair. Therefore, we hypothesize that the chronic sequelae of stroke, for example, axonal degeneration, inflammation, blood brain barrier dysfunction, and impaired paravascular clearance, initiate a myelin repair pathway that leads to the abnormal genesis of AD-like pathology in aged wt mice, and exacerbates pathology in aged AβPPL/S mice. Consequently, after we have further developed these two mouse models, we will use them to determine if the BACE1-dependent myelin repair pathway is necessary for stroke recovery, but antagonistically also leads to the generation of AD-associated pathology. Finally, we will determine if the small molecule p75 neurotrophin receptor (p75NTR) ligand, LM11A-31, which is currently in Phase 2a clinical trials for the treatment of AD, and which preserves myelinated axons following spinal cord injury, slows or prevents the development of m...