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Irene Knuesel"Reelin, amyloid-beta, and phospho-Tau – it takes three to tangle"

Abstract :

Besides the fundamental role of the extracellular glycoprotein Reelin in neuronal development and adult synaptic plasticity, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer’s disease (AD).
In vitro data revealed a biochemical link between Reelin-mediated signaling, Tau phosphorylation and amyloid precursor protein (APP) processing. To directly address the role of Reelin in amyloid-b plaque and Tau pathology in vivo, we crossed heterozygous Reelin knockout mice (reeler) with transgenic AD mice to investigate the temporal and spatial AD-like neuropathology. We demonstrate that a reduction in Reelin expression results in enhanced amyloidogenic APP processing, as indicated by the precocious production of amyloid-b peptides, the significant increase in number and size of amyloid-b plaques, as well as age-related aggravation of plaque pathology in double-mutant compared to single AD mutant mice. Numerous amyloid-b plaques accumulate in the hippocampal formation and neocortex LI of double-mutants, precisely in layers with strongest Reelin expression and highest accumulation of Reelin plaques in aged wild type mice. Moreover, concentric accumulations of phosphorylated Tau-immunoreactivity around amyloid-b plaques were evident in 15 months-old double-mutant versus single mutant mice. Silver stainings indicated the presence of neurofibrillary tangles, selectively associated with amyloid-b plaques and dystrophic neurites in the entorhinal cortex and hippocampus. Our findings suggest that age-related Reelin aggregation and concomitant reduction in Reelin-mediated signaling plays a proximal role in synaptic dysfunction associated with amyloid-b deposition, sufficient to enhance Tau phosphorylation and tangle formation in the hippocampal formation in aged Reelin-deficient transgenic AD mice.

Selected publications

Chronic clozapine treatment improves prenatal infection-induced working memory deficits without influencing adult hippocampal neurogenesis.Meyer U, Knuesel I, Nyffeler M, Feldon J.Psychopharmacology (Berl). 2009 Dec 30. [Epub ahead of print]
Appetitively motivated instrumental learning in SynGAP heterozygous knockout mice.Muhia M, Feldon J, Knuesel I, Yee BK.Behav Neurosci. 2009 Oct;123(5):1114-28.
Knuesel Irene, Nyffeler Myriel, Mormede Cecile, Muhia Mary, Meyer Urs, Pietropaolo Susanna B., Yee Benjamin K., Pryce Chrisopher R., LaFerla Frank M., Marighetto Aline and Feldon Joram (2007). Age-related accumulation of Reelin in amyloid-like plaques. Neurobiol Aging,

Aline Marighetto