Mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leu- koencephalopathy (CADASIL), a neurological condition characterized by small vessel disease and white mat- ter degeneration. Mutations in Presenilin 1 (PSEN1) are the most prevalent cause of early onset familial Alz- heimer?s disease (AD). Though CADASIL and PSEN1-associated AD are considered pure disease models, there is evidence of potential mechanistic overlap because PSEN1 function is required for the activation of Notch receptors including Notch3. Supporting this view, clinical studies showed substantial white matter dis- ease in PSEN1 mutation carriers and cerebral spinal fluid analyses of CADASIL patients show changes indica- tive of abnormal amyloid metabolism. We hypothesize that SVD and its associated white matter disease occurs due to dysregulation of homeostatic PSEN1/NOTCH3 pathways that preserve vessel and white matter integrity in adults under physiological conditions and are dysfunctional in familial forms of de- mentia. To test this hypothesis, we propose to leverage our animal models with Notch3 and Psen1 mutations. We will also conduct parallel studies in postmortem human tissue from PSEN1 and NOTCH3 mutation carriers to identify common pathobiological mechanisms. We propose two research aims:
Aim 1 : To examine functional links between PSEN1/NOTCH3 signaling and vascular degeneration us- ing mouse models and postmortem human tissue. We will use Notch3 and Psen1 mutant mouse models and postmortem human tissue from CADASIL and AD patients to examine the role of the PSEN1/NOTCH3 pathway on SVD. We will conduct studies in mice carrying single mutations and in mice carrying a CADASIL mutation in Notch3 and an AD-causing PSEN1 mutation.
Aim 2 : To investigate functional links between PSEN1/NOTCH3 signaling and brain white matter dis- ease. We will use Notch3 and PSEN1 mutant mouse models and postmortem human tissue to examine the role of the PSEN1/NOTCH3 pathway on white matter degeneration. We will conduct analyses in mice express- ing CADASIL mutations in mural cells and also in mice expressing mutant Notch3 in oligodendrocytes, another site of Notch3 expression that has been implicated in CADASIL pathobiology. These experiments will tell us the extent to which PSEN1/NOTCH3 dysfunction impact signaling in molecular pathways implicated in SVD and white matter degeneration potentially leading to the identification of novel therapeutic approaches.
This project uses in vivo models and postmortem human tissue to explore molecular mechanisms underlying vascular degeneration and white matter disease in conditions associated to vascular dementia and familial Alzheimer?s disease.