Since aging is the major risk factor in AD, we have investigated the putative changes in Reelin expression during normal and pathological forms of aging from mice to humans. Our data obtained from different species revealed a strikingly consistent pattern of age-related loss of Reelin-expressing neurons and concomitant accumulation in extracellular Reelin-positive deposits in the hippocampal formation. Both phenomena are associated with age-related episodic-like memory impairments in wild-type mice.
We further provided evidence that
- Proteolytic APP (amyloid precursor protein) fragments co-aggregate within and around Reelin-positive deposits
- Plaque pathology is accompanied by cholinergic axonal varicosities and a reduction in basal forebrain projection neurons; affecting both cholinergic and GABAergic cells
- a prenatal immune challenge accelerates plaque pathology significantly
Based on our recent findings we are currently elucidating the cellular and molecular mechanisms underlying the increased and accelerated amyloid-beta plaque and neurofibrillary tangle formation in mice with reduced Reelin expression.
Furthermore, we are investigating the role of inflammatory modulators on Reelin and APP processing, aimed at understanding the impact of pro-inflammatory cytokines on amyloid-beta plaque as well as neurofibrillary tangle formation.
In particular, we are interested in answering the following questions:
- Is the prenatal infection-induced increase in the expression of inflammatory cytokines in adult life causally involved in the formation of Reelin-positive deposits?
- Which are the immune modulators that selectively promote the formation of fibrillary deposits in the hippocampal formation?
- How are these immune modulators involved in the loss of Reelin-expressing neurons?
- What is the time course and proteomic composition of these extracellular proteinous aggregates?
- Is dysfunctional Reelin signaling (induced through genetic or environmental modification) sufficient to create a precursor condition for senile amyloid plaque deposition and neurofibrillary tangle formation?
- How does the dysfunctional Reelin signaling affect Tau hyperphosphorylation and neurofibrillary tangle formation in non-transgenic and transgenic AD mice?