Abstract
Amyloid-beta peptides (Abeta) are widely presumed to play a causal role in Alzheimer disease. Release of Abeta from the amyloid precursor protein (APP) requires proteolysis by the beta-site APP-cleaving enzyme (BACE1). Although increased BACE1 activity in Alzheimer disease brains and human (h) BACE1 transgenic (tg) mice results in altered APP cleavage, the contribution of these molecular alterations to neurodegeneration is unclear. We therefore used the murine Thy1 promoter to express high levels of hBACE1, with or without hAPP, in neurons of tg mice. Compared with hAPP mice, hBACE1/hAPP doubly tg mice had increased levels of APP C-terminal fragments (C89, C83) and decreased levels of full-length APP and Abeta. In contrast to non-tg controls and hAPP mice, hBACE1 mice and hBACE1/hAPP mice showed degeneration of neurons in the neocortex and hippocampus and degradation of myelin. Neurological deficits were also more severe in hBACE1 and hBACE1/hAPP mice than in hAPP mice. These results demonstrate that high levels of BACE1 activity are sufficient to elicit neurodegeneration and neurological decline in vivo. This pathogenic pathway involves the accumulation of APP C-terminal fragments but does not depend on increased production of human Abeta. Thus, inhibiting BACE1 may block not only Abeta-dependent but also Abeta-independent pathogenic mechanisms.
Highlights
Amyloid- peptides (A) are widely presumed to play a causal role in Alzheimer disease
Expression of BACE1 in Brains of mThy1-hBACE1 tg Mice—Microinjection of the mThy1-hBACE1 construct yielded four tg lines, three of which were selected for further analysis based on levels of hBACE1 mRNA determined by ribonuclease protection assay (RPA). hBACE1 mRNA levels in whole hemibrains of these tg lines were 3– 8-fold higher than in frontal cortex of humans without Alzheimer disease (AD), with the highest levels detected in line 1 (Fig. 1, A and B)
The present study demonstrates that increased activity of hBACE1 in neurons of tg mice is sufficient to elicit profound alterations in amyloid precursor protein (APP) metabolism, neurological deficits, and neurodegeneration
Summary
Neurological deficits were more severe in hBACE1 and hBACE1/ hAPP mice than in hAPP mice These results demonstrate that high levels of BACE1 activity are sufficient to elicit neurodegeneration and neurological decline in vivo. This pathogenic pathway involves the accumulation of APP C-terminal fragments but does not depend on increased production of human A. The potential pathogenic role of increased BACE activity has been investigated in vivo by analyzing the metabolism of APP in human (h) BACE transgenic (tg) mice (19 –22) These studies have shown that expression of hBACE1 at moderate levels in hAPP tg models results in increased generation of hAPP CTFs and A, which in some cases was associated with enhanced amyloid deposition. High levels of BACE1 activity significantly increased the cerebral accumulation of hAPP CTFs, but not of A, and caused prominent age-related neurodegeneration and neurological decline
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