Accumulation of murine amyloid-β mimics early Alzheimer's disease

Almost all mouse models of Alzheimer's disease use expression of human transgenes to trigger amyloid pathology. Krohn <italic toggle="yes">et al. introduce a new mouse model without transgene expression that, in common with patients with sporadic Alzheimer's disease, shows reduced amyloid-beta clearance. The model shows pathology reminiscent of early-stage Alzheimer's disease.Almost all mouse models of Alzheimer's disease use expression of human transgenes to trigger amyloid pathology. Krohn <italic toggle="yes">et al. introduce a new mouse model without transgene expression that, in common with patients with sporadic Alzheimer's disease, shows reduced amyloid-beta clearance. The model shows pathology reminiscent of early-stage Alzheimer's disease.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-beta 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-beta 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 ( ext-link-type="uri" xlink:href="http://www.erare.eu">www.erare.eu). Here, we show that mice that are double-deficient for neprilysin (encoded by <italic toggle="yes">Mme), one major amyloid-beta-degrading enzyme, and the ABC transporter ABCC1, a major contributor to amyloid-beta 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 x 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-beta 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-beta species/aggregates, i.e. monomers and small amyloid-beta oligomers. Thus, neprilysin x ABCC1 double-deficient mice present a new model for early effects of amyloid-beta-related mild cognitive impairment that allows investigations without artificial overexpression of inherited Alzheimer's disease genes.