Age-related accumulation of Reelin in amyloid-like deposits.
Accumulating evidence suggest that alterations in Reelin-mediated signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits. These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Abeta species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD.
Knuesel
Irene
I
Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. knuesel@pharma.uzh.ch
Nyffeler
Myriel
M
Mormède
Cecile
C
Muhia
Mary
M
Meyer
Urs
U
Pietropaolo
Susanna
S
Yee
Benjamin K
BK
Pryce
Christopher R
CR
LaFerla
Frank M
FM
Marighetto
Aline
A
Feldon
Joram
J
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002144:Callithrix; D015816:Cell Adhesion Molecules, Neuronal / Q000032:analysis / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000032:analysis / Q000378:metabolism*; D005260:Female; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D000091042:Reelin Protein; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000032:analysis / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics; D016875:tau Proteins / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; D016875:tau Proteins; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D018631:ras Proteins