Role of Complement Receptor Activation in a Mixed Dementia Model

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The coexistence of Alzheimer (AD) and cerebrovascular disease (CBVD), which defines Mixed Dementia (MxD) is present in many, if not most, of those diagnosed with AD. Hypertension is the major risk factor contributing to CBVD, driving small vessel disease (SVD), associated with white matter (WM) lesions characteristic of MxD, but the paucity of MxD models limits progress to understand mechanisms and advance therapeutics for this common disease. For example, drugs developed to clear amyloid (Abeta) may exacerbate CBVD, and fail to target poorly understood synergism between AD and CBVD. Our novel rat MxD model exhibits coexisting vascular and AD pathologies (AD transgenic), whereby hypertension and SVD exacerbate AD- associated aberrant neuroinflammation, mitochondrial dysfunction and tauopathy (Denver et al. 2019). Since recent clinical data, showing that WM damage is associated with the spread of tauopathy, not Abeta (Kapasi et al., 2022), this further validates our model. Further new data on seeding of MxD rats with tau fibrils, recapitulates tau spreading seen in human AD/MxD. The model was produced by breeding the Tg AD into a SHR-Stroke prone (SHRSP) rat background, the most widely studied model for vascular cognitive impairment and SVD, which exhibits a compromised neurovascular unit. Unlike mice, rats express all 6 tau isoforms and are more suitable than mice for complex imaging and behavioral testing, and assessing fluid biomarkers. The central hypotheses are: a) Complement factors are major components synergistically driving MxD and AD, and b) there is a positive feedback loop between tau pathogenesis and complement activation such that antagonizing either tau aggregation with structure-based inhibitors (Aim 2) or the complement cascade (Aim 3) will disproportionately reduce WM damage, tauopathy and executive function deficits in the hypertensive MxD model. Aim 1 will identify key MRI and laser captured pathology RNA expression profiles. 1A examines longitudinal changes of translatable MRI imaging measures (including SVD, demyelination, atrophy, and BBB leakage) that distinguish MxD from AD. In 1B, we perform IHC-guided laser capture microscopy dissection (LCM) and RNA seq in these MRI-characterized rats in 3 regions representing increased tauopathy (hippocampus), demyelination/WMH (dorsolateral/prefrontal cortex) and SVD (thalamus/putamen) to define MxD-specific, lesion- related pathways. Aims 2 and 3 investigate how AD and hypertension interact to influence a positive feedback loop between complement and tauopathy. Aim 2 uses a structure-based tau aggregation inhibitor that we characterized in tau mouse models. Aim 3 uses a state-of-the-art orally bioavailable and brain penetrant small molecule inhibitor (see letters), to investigate the causal role of C5aR activation that can drive tauopathy, BBB breakdown and WM loss. Outcomes. Outcomes focus on regional biochemical and histological changes in BBB, myelination, neurodegeneration, neuroinflammation and executive function deficits. CSF/plasma biomarkers are assessed: specifically validated AD biomarkers (ptau, NFL, Abeta40/42) and those associated with brain inflammation (GFAP, AQP4 (astrocytic endfoot protein)) or WMH (complement factors C3b, and Bb) and neuroprotection (BDNF) to identify their role in the tau-complement C5a feedback loop. Interpretation: Advances may include demonstration of hypertension-enhanced tauopathy and/or C5aR and tauopathy-enhanced BBB breakdown and one or more effective new treatments. Alternatively, tau aggregate inhibitors may not impede BBB and inflammatory pathogenesis, suggesting a minor role for the tau-inflammation-BBB loop and arguing for combination therapies. Which upstream C3-related inflammatory or downstream C5b components are inhibited by C5aR inhibitors will provide important insight into tau-complement feedback interactions in MxD. RNAseq is likely to fill major knowledge gaps in understanding mechanisms of SVD that drive conversion from AD pathology to onset of cognitive decline. Our proposal is strengthened by a multidisciplinary team with expertise in stroke, MRI imaging, LCM /RNAseq, complement activation, CBVD/AD neuropathology, and executive dysfunction.