This revised proposal utilizes our recently described novel model of Mixed Dementia (MxD) (Denver et al. 2019), the most prevalent dementia, yet MxD subjects are often excluded from AD trials. There is a paucity of models with coexisting vascular and Alzheimer's (AD) pathologies, in addition to a lack of consensus in neuropathological (or neuropsychiatric) diagnostic criteria for MxD. Therefore, this proposal seeks to identify synergistic and independent interactions between AD and hypertension-associated cerebrovascular disease factors in pathology, behavior and biomarkers and modulation by treatment, sex and ApoE isotype. The SHR- Stroke prone (SHRSP) rat is the most widely studied model for vascular cognitive impairment (VCI) and develop vascular pathology and a compromised neurovascular unit. We used this to create ?SHRSPFAD? rats by breeding in mutant APP/PS1 transgenes. Our SHRSPFAD rat shows multiple features of MxD including tauopathy, recently speculated to be increased disproportionately to amyloid in MxD. We propose four aims, which include methods to address limitations of one of the controls: normotensive WKY rats (founder of SHRSP), which is used as the non-hypertensive control, but poses the same limitations as AD models with homozygous colonies (e.g. ApoETR, 3xTg mice etc.), so the aims attempt to overcome this limitations, such as exploring how severity of hypertension affects the synergism between AD and hypertension within phenotype.
Aim 1 determines if further increasing hypertension, using high salt diet, used with SHSRP to exacerbate hypertension (and lower VEGF and VGF) affects aging or sex modulation of synergism between AD and hypertension.
Aim 2 also addresses this limitation, by reducing hypertension with Angiotensin II Receptor Blockers (ARBs), known to protect the BBB and reduce dementia risk.
Thus Aim 2 validates hypertensive-dependent effects on pathology, biomarkers and behavior using ARBs in the SHRSPFAD model.
Aims 3 and 4 address effects of ApoE4 the main genetic AD risk factor (notably in women), also impactsing vasculature. Hypertension in post- menopausal female E4 carriers creates a high dementia risk unlike rodents that lack a precipitous drop in antihypertensive and neuroprotective estrogen. Therefore Aim 3: characterizes a novel ApoE SHRSPFAD model and determines the impact of losartan and the anti-estrogen receptors involved in BP control. Since comorbidities in MxD introduce multiple pathways, polypharmacy is necessary in the clinic. Disruption of VEGF signaling is seen in VCI and with ApoE4, so we evaluate the effects of ARB with the FDA approved PPD3 inhibitor Cilostazol, which restores VEGF signaling, protecting the neurovascular unit. Thus, Aim 4 determines efficacy of the combination therapy ARB and Cilostazol.
Aims 1 -4 variables: vascular- dependent and cognitive variables, bulk and glia- and endothelial-specific RNAseq analysis, tau, A?, demyelination, mitochondrial deficits and brain- derived exosomal plasma biomarkers associated with neuroinflammation and disruption of the perivascular unit.
People with uncontrolled hypertension have an almost three-fold increased risk for dementia, and if they are carriers of apolipoprotein E4 (ApoE4, that is, 25% of population), then they have 13 fold increased risk for dementia (female E4 carriers already have twice as much as risk as male E4 carriers). Despite the fact that 80% of people with Alzheimer's also have cerebrovascular diease (mixed dementia) and despite the knowledge that people with mixed dementia have serious adverse effects to amyloid clearing drugs, there is a paucity or lack of preclinical models and none with ApoE3 or ApoE4. We have now developed a novel rat model for mixed dementia, which has several features of mixed dementia including energy deficits, and including ApoE3 and ApoE4: rats have additional advantages over mice because of a more complex brain and larger cerebrospinal fluid and plasma volumes, making it a better preclinical model.
