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Alzheimer’s disease; APP-transgenic mice; gamma secretase inhibitor; two-photon imaging; dendritic spines;
axonal boutons
Abstract:
The loss of synapses is a strong histological correlate of the cognitive decline in Alzheimer’s disease (AD). Amyloid bpeptide (Ab),
a cleavage product of the amyloid precursor protein (APP), exerts detrimental effects on synapses, a process thought to be causally
related to the cognitive deficits in AD. Here, we used in vivo two-photon microscopy to characterize the dynamics of axonal
boutons and dendritic spines in APP/Presenilin 1 (APPswe/PS1L166P)–green fluorescent protein (GFP) transgenic mice. Time-lapse
imaging over 4 weeks revealed a pronounced, concerted instability of pre- and postsynaptic structures within the vicinity of
amyloid plaques. Treatment with a novel sulfonamide-type g-secretase inhibitor (GSI) attenuated the formation and growth of new
plaques and, most importantly, led to a normalization of the enhanced dynamics of synaptic structures close to plaques. GSI
treatment did neither affect spines and boutons distant from plaques in amyloid precursor protein/presenilin 1-GFP (APPPS1-GFP)
nor those in GFP-control mice, suggesting no obvious neuropathological side effects of the drug.
