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Accumulation of murine amyloid-ß mimics early Alzheimer's disease.

Authors: Krohn, Markus  Bracke, Alexander  Avchalumov, Yosef  Schumacher, Toni  Hofrichter, Jacqueline  Paarmann, Kristin  Fröhlich, Christina  Lange, Cathleen  Brüning, Thomas  von Bohlen Und Halbach, Oliver  Pahnke, Jens 
Citation: Krohn M, etal., Brain. 2015 Aug;138(Pt 8):2370-82. doi: 10.1093/brain/awv137. Epub 2015 May 18.
Pubmed: (View Article at PubMed) PMID:25991605
DOI: Full-text: DOI:10.1093/brain/awv137

Amyloidosis mouse models of Alzheimer's disease are generally established by transgenic approaches leading to an overexpression of mutated human genes that are known to be involved in the generation of amyloid-ß in Alzheimer's families. Although these models made substantial contributions to the current knowledge about the 'amyloid hypothesis' of Alzheimer's disease, the overproduction of amyloid-ß peptides mimics only inherited (familiar) Alzheimer's disease, which accounts for <1% of all patients with Alzheimer's disease. The inherited form is even regarded a 'rare' disease according to the regulations for funding of the European Union ( Here, we show that mice that are double-deficient for neprilysin (encoded by Mme), one major amyloid-ß-degrading enzyme, and the ABC transporter ABCC1, a major contributor to amyloid-ß clearance from the brain, develop various aspects of sporadic Alzheimer's disease mimicking the clinical stage of mild cognitive impairment. Using behavioural tests, electrophysiology and morphological analyses, we compared different ABC transporter-deficient animals and found that alterations are most prominent in neprilysin × ABCC1 double-deficient mice. We show that these mice have a reduced probability to survive, show increased anxiety in new environments, and have a reduced working memory performance. Furthermore, we detected morphological changes in the hippocampus and amygdala, e.g. astrogliosis and reduced numbers of synapses, leading to defective long-term potentiation in functional measurements. Compared to human, murine amyloid-ß is poorly aggregating, due to changes in three amino acids at N-terminal positions 5, 10, and 13. Interestingly, our findings account for the action of early occurring amyloid-ß species/aggregates, i.e. monomers and small amyloid-ß oligomers. Thus, neprilysin × ABCC1 double-deficient mice present a new model for early effects of amyloid-ß-related mild cognitive impairment that allows investigations without artificial overexpression of inherited Alzheimer's disease genes.


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CRRD Object Information
CRRD ID: 13801010
Created: 2018-10-25
Species: All species
Last Modified: 2018-10-25
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.