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The role of inflammatory modulators on Reelin-dependent signaling in the etiology of late-onset Alzheimer's disease

English title The role of inflammatory modulators on Reelin-dependent signaling in the etiology of late-onset Alzheimer's disease
Applicant Knüsel Irene
Number 117806
Funding scheme Project funding
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2007 - 30.09.2010
Approved amount 260'000.00
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Keywords (6)

mus musculus; inflammatory cytokines; prenatal infection; PolyI:C; aging; amyloid-beta plaques

Lay Summary (English)

Lead
Lay summary
Alzheimer's disease (AD) is the most common type of dementia, characterized by progressive cognitive decline and severe neurodegeneration. Neuropathological hallmarks include proteinous aggregates in the form of amyloid plaques, mainly composed of amyloid-b peptides, and neurofibrillary tangles, consisting of abnormally phosphorylated Tau. Although investigations of the genetic basis of the disease have greatly enhanced our understanding of AD biology, dominant genetic defects account only for a small percentage of cases. The vast majority are sporadic late-onset AD cases with largely unknown etiology. The fact that both forms of AD are characterized by the same neuropathological hallmarks points to the importance of modulatory factors involved in the pathophysiology of the disease.One of these potential modulators is Reelin, a large extracellular glycoprotein with a fundamental role in neuronal positioning during brain development. This highly conserved protein is also a pivotal synaptic regulator which indirectly exerts broad control over synaptic function and plasticity in the adult brain. New insights into the molecular mechanisms by which Reelin may affect the formation of plaques and tangles have recently been provided by the observations that Reelin-mediated signaling affects amyloid precursor protein (APP) processing and Tau phosphorylation.We have recently demonstrated that Reelin expression is strongly affected by age, the major risk factor of AD. Our data obtained from different species revealed a strikingly consistent pattern of reduction in Reelin-expressing neurons and concomitant accumulation in amyloid-like deposits in the hippocampal formation. We provided evidence that a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits. Our findings of an acceleration of senescence, the sustained elevation of inflammatory cytokines in the adult hippocampus, and the failure of removing the extracellular aggregates after early brain inflammation point to a critical role of the immune system during aging and suggest that dysfunctional immune modulators may be a critical driving force of the neuropathology of AD. We therefore propose to investigate whether a prenatal infection-induced increase in the expression of inflammatory cytokines in adulthood is causally involved in the precocious formation of Reelin-positive plaques and the promotion of fibrillary deposits in wild type mice. We will determine the time course of formation and proteomic composition of these deposits, and aim to elucidate the cellular mechanisms of the increased neuronal vulnerability by examining short- and long-term effects of inflammatory modulators on the Reelin signaling affecting neurotransmitter receptor clustering, APP processing, Tau phosphorylation, and protein degradation. Through this, the project is expected to demonstrate that manipulation of inflammatory pathways altering the Reelin signaling pathway is a critical driving force of late-onset Alzheimer’s disease pathology.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
132629 Prenatal infection: A novel link between brain development, inflammation and aging-associated neurodegeneration 01.10.2010 Project funding

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