Mixed dementia is a complex form of dementia in which heterogeneous disease states co-exist, the most common being pathologic characteristics of vascular dementia (VaD), such as chronic stroke infarcts, alongside pathologic characteristics of Alzheimer?s disease (AD). It is unknown precisely how many patients presently diagnosed with a particular type of dementia actually have mixed dementia, however post-mortem analyses suggest that the condition may be present in nearly 50% of patients clinically diagnosed with AD. Yet 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 of mixed dementia, and there are no proven disease modifying therapies. To address this need, the goal of this proposal is to test if a first-in-class small molecule, orally bioavailable p75 neurotrophin receptor (p75NTR) ligand, LM11A-31, currently in Phase IIa clinical trials for the treatment of AD, also has efficacy in two different mouse models of post-stroke mixed dementia. The first, is an innovative model of post-stroke mixed dementia in which in the weeks following stroke, aged wildtype (wt) mice exhibit cholinergic neurodegeneration along with the appearance of neuritic plaques resembling those found in AD (Aim 1). The second, is a transgenic mouse model of mixed dementia in which aged A?PPL/S mice that have undergone a stroke develop more severe AD pathology than their age-matched counterparts (Aim 2). In both of these models, mice also develop delayed cognitive impairments in the weeks after stroke. Positive results obtained here would be the first validation that p75NTR is an effective therapeutic target in two post-stroke mixed dementia models, and could fast-track LM11A-31 into post-stroke mixed dementia clinical testing.
Vasculardementiaresultingfromcerebrovascularpathologyisthesecondmostprevalenttypeofdementiaafter Alzheimer?sdisease(AD),andbotharemorelikelytodevelopwithage.Mixeddementiaistheco-existenceof cerebrovascularandADneuropathology,andposesgrowingpersonal,societal,andeconomicburdens,withno provendiseasemodifyingtherapy.Therefore,thegoalofthisresearchistotestafirst-in-classp75neurotrophin receptor(p75NTR)ligand,currentlyinPhaseIIaclinicaltrialsforAD,intwodifferentmousemodelsofpost-stroke mixeddementia.Positiveresultsobtainedinthesestudieswouldbethefirstvalidationthatp75NTRisaneffective therapeutictargetforpost-strokemixeddementia,andcouldrapidlyadvanceLM11A-31intoclinicaltestingfor dementiawithmixedinfarctandADpathologies.
