| No APP-alone mouse gets neurodegeneration resembling that seen in the human AD brain, i.e. with so-called "neuritic" plaques, tauopathy, spongiopathy and widespread neuronal death. This is why researchers now most often use the 5XFAD mouse, which has APP with three mutations, and presenilin with two mutations (hence 5 FAD mutations) [0]. Note however that mutated presenilin alone is enough to cause neurodegeneration in mice, such mice however do not accumulate amyloid, which is why mutated APP in added to make the pathology more "realistic". As to Aβ42, there are mutations in APP which cause familial AD, but produce exclusively Aβ40, e.g. APP A673V [1]. Note also that most studies report alterations in the ratio of Aβ42 to Aβ40, precisely because effects on the levels of Aβ production are inconsistent across APP mutations. Nevertheless..... and despite my obvious skepticism towards the amyloid toxicity hypothesis, the mutations in APP that cause AD all cluster in or near the region of the protein that is Aβ. There must be a reason for that. It is also in contrast to presenilin, where the mutations are distributed throughout the molecule, indication a loss of presenilin function causes AD. One alternate explanation to Aβ or oligomer toxicity is proposed toxicity of the immediate precursor to Aβ, i.e. the APP C-terminal fragment (CTF), see for example the recent paper below and references therein [2]. [0] https://www.alzforum.org/research-models/5xfad-b6sjl [1] A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis https://pmc.ncbi.nlm.nih.gov/articles/PMC2728497/ [2] APP β-CTF triggers cell-autonomous synaptic toxicity independent of Aβ https://pmc.ncbi.nlm.nih.gov/articles/PMC12017768/ |