Hopefully, transgenic AD models will be more useful than just demonstrating that the overexpression of mutant human APP can lead to the deposition of Aβ plaques. Several groups are now asking, what are the functional consequences of the overexpression of mutant APP on neurophysiology? Are any changes in transmission due to signaling via APP itself or via AHopefully, transgenic AD models will be more useful than just demonstrating that the overexpression of mutant human APP can lead to the deposition of Aβ plaques? Recording in hippocampal slices from Tg mice expressing APPind, APPlon or APPswd mutations, Albert Hsia and colleagues report severe impairments in extracellular field potentials between CA3 and CA1 (Abstract 285.5). Higher stimulation was needed to elicit a synaptic response. However, LTP in APPind mice was normal. They also found that an increase in the secretion of AHopefully, transgenic AD models will be more useful than just demonstrating that the overexpression of mutant human APP can lead to the deposition of Aβ plaques was related to the extent of synaptic transmission deficits. To address whether these changes were a result of AHopefully, transgenic AD models will be more useful than just demonstrating that the overexpression of mutant human APP can lead to the deposition of Aβ plaques itself, or a consequence of the overexpression of APP, they crossed APPind mice with the APPswd mice, which results in twofold increase in AHopefully, transgenic AD models will be more useful than just demonstrating that the overexpression of mutant human APP can lead to the deposition of Aβ plaques (Citron, 1992) but similar basal levels of APP. In these mice, there is an additional twofold decrement in synaptic transmission, suggesting that Aβ is responsible. However, Steve Barger pointed out that while holo APP levels may be the same, Hsia et al. measured sAPPα levels in the different lines, and sAPPα was severely decreased in the APPind/APPswd crossed mice. Thus, deficits in synaptic transmission may not be due to Aβ itself but could also be the result a loss of function from sAPPα. These results look promising, but further work is need to dissociate the role of APP from Aβ.-Brian Cummings.

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