PD Dr. Irene Knuesel

 

Main Goals, Keywords

The goal of our research is to understand the neurobiological processes dissociating normal from pathological forms of aging and which are responsible for triggering the molecular cascades leading to neurodegeneration, accelerated senescence and cognitive impairments. We are using a combination of in-vitro and in-vivo strategies, including molecular, biochemical, immunological, immunohistochemical, ultrastructural, pharmacological, and behavioural paradigms in order to model the onset and progression of the disease in mice.

Keywords: Aging, Alzheimer’s disease, neurodegeneration, cognitive decline, hippocampal formation, prenatal infection, inflammatory cytokines, Reelin-mediated signaling, amyloid-beta plaques, hyperphosphorylation of Tau, neurofibrillary tangles, cell death

Group Members

1 group leader, 1 Postdoc, 2 Ph.D. students, 2 MSc students, 1 technician

Previous and Current Research

Although investigations of the genetic basis have greatly enhanced our understanding of the biology of Alzheimer’s disease (AD), dominant genetic defects account only for a small percentage of cases. The vast majority are sporadic AD cases with largely unknown etiology. The fact that both early- and late-onset 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. 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 neuropathology in mice to man: Reelin expression declines during aging and the protein accumulates in amyloid-like deposits in the hippocampal formation. 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

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.

Figure:Reelin-positive cell and deposits (green) in close association with astorcytes (red) in the CA area of a 12 month old wild type mouse.

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 reduced Reelin-mediated signaling in tgAD mice (reln/app; mice heterozygote for the reelin gene and over-expressing the hAPP_swe,arc mutation, Kocherhans et al., 2010) favors amyloidogenic APP processing, and Tau hyperphosphorylation in aged double compared to single transgenic (app) mice.

A-C: Anti phospho-Tau (pT205) immunoreactivity in 15 mo app or reln/app mice. Scale bars upper row: 30 mm, lower row = 20 mm.

Future Projects

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

Techniques and Equipment

Immunohistochemistry, electron microscopy, cell culture, primary neuronal cultures, confocal microscopy, laser dissection microscopy, tissue fractionation, immunoprecipitation and Western blot analysis, recombinant DNA technology, real-time PCR, mass spectrometry, behavioural analysis of mice.

Vibratome, cryostat and sliding microtomes for histological sections; epifluorescence and confocal microscopes, image analyses systems including Explora Nova stereology software; cell culture facilities; state-of-the art molecular biology and biochemistry equipments.

Selected Publications

• Krstic D, Pfister S, Notter T, Knuesel I. Decisive role of Reelin signaling during early stages of Alzheimer's Disease. Neuroscience. 2013 Apr 27. doi:pii: S0306-4522(13)00367-9. 10.1016/j.neuroscience.2013.04.042. [Epub ahead of print]
• Krstic D, Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat Rev Neurol. 2013 Jan;9(1):25-34. doi: 10.1038/nrneurol.2012.236. Epub 2012 Nov 27.
• Krstic D, Madhusudan A, Doehner J, Vogel P, Notter T, Imhof C, Manalastas A, Hilfiker M, Pfister S, Schwerdel C, Riether C, Meyer U, Knuesel I. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflammation. 2012 Jul 2;9(1):151. [Epub ahead of print]
• Doehner J, Genoud C, Imhof C, Krstic D, Knuesel I. Extrusion of misfolded and aggregated proteins--a protective strategy of aging neurons? Eur J Neurosci. 2012 Jun;35(12):1938-50. doi: 10.1111/ j.1460-9568.2012.08154.x.

Selected Lectures, Seminars, Colloquia

• Struktur und Funktion des ZNS und der Sinnesorgane (Humanbiologie)
• Praktikum Neurowissenschaften
• ZNZ Advanced Course in Neurobiology

Funding

Swiss National Science Foundation, National Center for Competence in Research (NCCR) „Neural Plasticity and Repair", Hartmann-Müller Stiftung, Novartis Stiftung für medizinisch-biologische Forschung, Schweizerische Akadmie für Medizinische Wissenschaften (SAMW), Gottfried und Julia Bangerter-Rhyner Stiftung

URL

http://www.pharma.uzh.ch/