PROJECT SUMMARYEvidence in humans suggests that vascular risk factors such as stroke increase the risk of or in some caseshave a synergistic effect on the development of Alzheimer's disease (AD). Most vascular dementia (VaD) andAD mixed dementia patients exhibit more varied pathology with respect to -amyloid (A) accumulation brainatrophy and neurodegeneration than typical pure AD patients. At present the precise number of patientspresently diagnosed with a particular type of dementia that actually have mixed dementia is not known; howeverpost-mortem analyses suggest that the condition may be present in over half of patients clinically diagnosed withAD. Furthermore despite the frequent co-existence of VaD and AD little is known about how these diseasesinfluence 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 ofmixed dementia that can be used to investigate how the long-lasting pathological sequelae of ischemic strokeimpact 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 micecompared to young adult mice in the months following ischemic stroke. This behavioral manifestationcorresponds with increased brain atrophy and cholinergic degeneration as well as a focal increase in A and taupathology in areas of axonal degeneration and white matter tracts of the ipsilateral hemisphere. In contrast ourpreliminary data show that in a mixed dementia model using aged transgenic A precursor protein transgenicmice (APPL/S) that ischemia exacerbates behavioral deficits and that this correlates with a global increase inA and tau pathology compared to APPL/S mice that undergo a sham procedure. Furthermore in both modelsthe stroke-induced AD pathology co-localized with the presence of or increases in -secretase (BACE) 1 andneuregulin (NRG) 1 type III both of which are necessary for myelin repair. Therefore we hypothesize that the chronic sequelae of stroke for example axonal degenerationinflammation blood brain barrier dysfunction and impaired paravascular clearance initiate a myelin repairpathway that leads to the abnormal genesis of AD-like pathology in aged wt mice and exacerbates pathology inaged APPL/S mice. Consequently after we have further developed these two mouse models we will use themto determine if the BACE1-dependent myelin repair pathway is necessary for stroke recovery butantagonistically also leads to the generation of AD-associated pathology. Finally we will determine if the smallmolecule p75 neurotrophin receptor (p75NTR) ligand LM11A-31 which is currently in Phase 2a clinical trials forthe treatment of AD and which preserves myelinated axons following spinal cord injury slows or prevents thedevelopment of mixed dementia-related behavioral and pathological abnormalities in mice that have undergonea stroke.