Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice

Abstract

The aspartyl protease ␤-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates processing of amyloid precursor protein (APP) into amyloid ␤ (A␤) peptide, the major component of Alzheimer disease (AD) plaques. To determine the role that BACE1 plays in the development of A␤-driven AD-like pathology, we have crossed PDAPP mice, a transgenic mouse model of AD overexpressing human mutated APP, onto mice with either a homozygous or heterozygous BACE1 gene knockout. Analysis of PDAPP/BACE(؊/؊) mice demonstrated that BACE1 is absolutely required for both A␤ generation and the development of age-associated plaque pathology. Furthermore, synaptic deficits, a neurodegenerative pathology characteristic of AD, were also reversed in the bigenic mice. To determine the extent of BACE1 reduction required to significantly inhibit pathology, PDAPP mice having a heterozygous BACE1 gene knock-out were evaluated for A␤ generation and for the development of pathology. Although the 50% reduction in BACE1 enzyme levels caused only a 12% decrease in A␤ levels in young mice, it nonetheless resulted in a dramatic reduction in A␤ plaques, neuritic burden, and synaptic deficits in older mice. Quantitative analyses indicate that brain A␤ levels in young APP transgenic mice are not the sole determinant for the changes in plaque pathology mediated by reduced BACE1. These observations demonstrate that partial reductions of BACE1 enzyme activity and concomitant A␤ levels lead to dramatic inhibition of A␤-driven AD-like pathology, making BACE1 an excellent target for therapeutic intervention in AD.Alzheimer disease is the major cause of dementia in elderly people and is characterized by progressive cognitive decline. There is no cure, current treatments offer only temporary relief, and death invariably ensues. Substantial evidence suggests that the amyloid ␤ peptide (A␤) 6 is the cause of Alzheimer disease (AD)-associated neuropathology (1). A␤ is derived by sequential proteolysis of the amyloid precursor protein (APP) through ␤-and ␥-secretase activities and is widely deposited in amyloid plaques in the brains of individuals with AD (2, 3). Therefore, inhibiting the action of one or both of these enzymatic activities may provide inaugural disease-modifying therapies for AD.The aspartyl protease BACE1 is the primary ␤-secretase (4 -6) and is the sole ␤-secretase in mice, since its genetic ablation fully abolishes A␤ generation (7-9). Early reports indicated that BACE1 knock-out animals are healthy and fertile, with no histological pathologies, suggesting that inhibition of BACE1 for therapeutic intervention in AD would have no mechanism related toxicities (7, 9, 10). In contrast, recent reports of partially penetrant lethality and cognitive deficits in BACE1 knock-out animals do suggest potential liabilities of complete BACE1 inhibition (11, 12). As the initiating enzyme in the generation of A␤, BACE1 is a key drug target and would be predicted to abrogate pathologies associated with any form of A␤. To avoid potential side effects re...

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

“…3). In in vivo model systems, similar magnitudes of Aβ reductions are sufficient to prevent or halt Aβ plaque accumulation (53,54).…”

Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase

“…The contrast between BACE1's essential role in cognitive, emotional and synaptic functions 19,20 and its pathophysiological dysregulation in Alzheimer's disease 38,39 highlights the regulatory complexity of this protein. Owing to the consequences of its dysregulation, BACE1 gene expression must normally maintain tight robust regulatory control.…”

“…Even small changes in BACE1 activity may lead to a long-lasting and chronic process of Aβ 1-42 accumulation in the Alzheimer's disease brain 38,40 . Our current findings provide further evidence for a feed-forward mechanism of stress-dependent and activity-dependent 41 Aβ 1-42 production.…”

β-Site Amyloid Precursor Protein (APP)-cleaving Enzyme 1 (BACE1)-deficient Mice Exhibit a Close Homolog of L1 (CHL1) Loss-of-function Phenotype Involving Axon Guidance Defects

“…Second, BACE1 null phenotypes arise only in the BACE1 Ϫ/Ϫ homozygotes, equivalent to 100% BACE1 inhibition, but not in BACE1 ϩ/Ϫ heterozygotes. Based on AD mouse model studies, it is hypothesized that 50% BACE1 inhibition is necessary to delay or prevent amyloid deposition (17,57). Finally, many if not all the BACE1 null phenotypes may be related to development in the absence of BACE1, whereas the fully developed adult may not require BACE1 activity.…”