Abstract
Reducing levels of the aggregation-prone Aβ peptide that accumulates in the brain with Alzheimer’s disease (AD) has been a major target of experimental therapies. An alternative approach may be to stabilize the physiological conformation of Aβ. To date, the physiological state of Aβ in brain remains unclear, since the available methods used to process brain tissue for determination of Aβ aggregate conformation can in themselves alter the structure and/or composition of the aggregates. Here, using synchrotron-based Fourier transform infrared micro-spectroscopy, non-denaturing gel electrophoresis and conformational specific antibodies we show that the physiological conformations of Aβ and amyloid precursor protein (APP) in brain of transgenic mouse models of AD are altered before formation of amyloid plaques. Furthermore, focal Aβ aggregates in brain that precede amyloid plaque formation localize to synaptic terminals. These changes in the states of Aβ and APP that occur prior to plaque formation may provide novel targets for AD therapy.
Highlights
Reducing levels of the aggregation-prone Ab peptide that accumulates in the brain with Alzheimer’s disease (AD) has been a major target of experimental therapies
AD transgenic Tg19959 mice harbouring two familial AD mutations in the amyloid precursor protein (APP), which show initial amyloid plaques at or just before 3 months of age12. mFTIR spectral maps were recorded in chemically unprocessed brain sections of Tg19959 and wild-type mice at 1, 2 and 3 months of age (Fig. 1)
We verified that the sample preparation used for our mFTIR imaging of cryo-dried brain tissue did not introduce artificial b-sheet formation, since change of b-sheet did not occur with cryo-drying of synthetic Ab42 preparations (Supplementary Fig. 1)
Summary
Reducing levels of the aggregation-prone Ab peptide that accumulates in the brain with Alzheimer’s disease (AD) has been a major target of experimental therapies. Using synchrotron-based Fourier transform infrared micro-spectroscopy, non-denaturing gel electrophoresis and conformational specific antibodies we show that the physiological conformations of Ab and amyloid precursor protein (APP) in brain of transgenic mouse models of AD are altered before formation of amyloid plaques. Focal Ab aggregates in brain that precede amyloid plaque formation localize to synaptic terminals These changes in the states of Ab and APP that occur prior to plaque formation may provide novel targets for AD therapy. To analyse the early changes in Ab structure in brains of AD transgenic mouse models of b-amyloidosis, we used the nondestructive techniques of synchrotron-based two-dimensional Fourier transform infrared micro-spectroscopy imaging (mFTIR) and blue native polyacrylamide gel electrophoresis (BN-PAGE) complemented with 3D confocal immunofluorescence microscopy. Using BN-PAGE we show the loss of a low molecular weight Ab complex and emergence of higher weight Ab and APP complexes in AD transgenic mouse brains that occur concomitant with this pre-plaque rise in b-sheet content by mFTIR
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