Abstract
Neprilysin-sensitive Synapse-associated Amyloid-β Peptide Oligomers Impair Neuronal Plasticity and Cognitive Function
Highlights
Neprilysin Deficiency Affects Levels of A but Not amyloid precursor protein (APP) or Other Fragments—In APP transgenic mice cross-bred with neprilysin-deficient mice (NEPϪ/ϪAPPϩ mice), the quantities of APP or other APP fragments remained unaltered, there was no difference from control in the steady-state levels of full-length APP, secreted forms of APP (sAPP)␣, sAPP, the CTF-, CTF-␣, or CTF-␥/⑀ (Fig. 1), and the amount of A was markedly and significantly elevated (Fig. 2, A and B)
In addition to APP transgenic mice with neprilysin, a set of wild-type and neprilysin-deficient mice without the APP transgene serves as a relevant triple control on evaluating neuronal functions
Much less is understood about the possible relationship between a local increase in synaptic A and a reduction of A-catabolic activity involving neprilysin in the brain; it has been observed that neprilysin in the hippocampus and cerebral cortex is down-regulated upon normal aging [14, 15] and from an early stage of Alzheimer disease (AD) development [15,16,17]
Summary
A, amyloid- peptide; AD, Alzheimer disease; APP, amyloid precursor protein; sAPP, secreted forms of APP; LTP, long-term potentiation; CTF, C-terminal fragment of APP; EPSP, excitatory postsynaptic potential; IEM, immunoelectron microscopy; CA1, CA1 stratum radiatum of hippocampus; OML, outer molecular layer of the dentate gyrus; DG, dentate gyrus; ELISA, enzyme-linked immunosorbent assay; oligomer-IR, oligomer immunoreactions; ANOVA, analysis of variance; NEP, neprilysin. In vivo as well as cognitive abnormality in the rat (29 –31). It is necessary to consider whether A oligomers placed exogenously in ventricles diffuse sufficiently into hippocampal parenchyma and at which neuronal sites they act to influence synaptic and neuronal activities. To clarify a possible connection between a reduction in neprilysin activity and impairment of synaptic and cognitive functions, we cross-bred APP transgenic mice (APP23) [32] with neprilysin-deficient mice [33], analyzed A accumulation biochemically and histologically in the brains of the cross-bred mice at the age of 13–16 weeks, and related the local elevation of A oligomers with dysfunction of hippocampal synaptic plasticity by using an in vivo recording technique and with abnormalities in cognitive function by using a battery of learning and memory behavior tests
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