BACE1 and Mutated Presenilin-1 Differently Modulate Aβ40 and Aβ42 Levels and Cerebral Amyloidosis in APPDutch Transgenic MiceHerzig M.C. · Paganetti P. · Staufenbiel M. · Jucker M.
aDepartment of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; bDepartment of Neuropathology, Institute of Pathology, University of Basel, and cNervous System Research, Novartis Institutes for Biomedical Research, Basel, Switzerland
APPDutch transgenic (tg) mice develop cerebral amyloid angiopathy (CAA) that consists mainly of AβDutch40, with virtually no parenchymal amyloid plaques. To modulate cerebral amyloidosis, we crossbred APPDutch mice with either BACE1 tg mice to increase total AβDutch, or with G384A-mutated PS1 tg mice to elevate the ratio of AβDutch42 to AβDutch40. We analyzed all mice at 22 months of age. Compared to APPDutch mice, double-tg APPDutch/BACE1 mice revealed increased CAA mainly due to extensive vascular amyloid accumulation in the thalamus. In addition, they developed parenchymal amyloid in cortex and subiculum. In contrast, APPDutch/G384A-PS1 mice showed extensive, predominantly parenchymal amyloid throughout the entire brain, interestingly, even in the thalamus. The amyloid, composed largely of AβDutch42, was different compared to that in APPDutch/BACE1 mice which was composed mainly of AβDutch40. In summary, these mouse models reveal a broad variety and region-specificity of parenchymal versus vascular cerebral amyloid. This is partially explained by the absolute amount of neuronally produced AβDutch42 and AβDutch40 and ratio between the two. We conclude that the absolute levels of Aβ in combination with the ratio of Aβ42 to Aβ40 play a key role in determining the cerebral compartment and brain region in which Aβ is deposited.
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