β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels Become Elevated in Neurons around Amyloid Plaques: Implications for Alzheimer's Disease Pathogenesis

Abstract

␤-Site amyloid precursor protein cleaving enzyme 1 (BACE1) (␤-secretase) initiates generation of ␤-amyloid (A␤), which plays an early role in Alzheimer's disease (AD). BACE1 levels are increased in postmortem AD brain, suggesting BACE1 elevation promotes A␤ production and AD. Alternatively, the BACE1 increase may be an epiphenomenon of late-stage AD. To distinguish between these possibilities, we analyzed BACE1 elevation using a highly specific BACE1 antibody, BACE-Cat1, made in BACE1Ϫ/Ϫ mice, which mount a robust anti-BACE1 immune response. Previous BACE1 immunohistochemical studies lack consistent results because typical BACE1 antibodies produce nonspecific background, but BACE-Cat1 immunolabels BACE1 only. BACE1 elevation was recapitulated in two amyloid precursor protein (APP) transgenic mouse lines. 5XFAD mice form amyloid plaques at young ages and exhibit neuron loss. In contrast, Tg2576 form plaques at a more advanced age and do not show cell death. These two mouse lines allow differentiation between early A␤-induced events and late phenomena related to neuron death. BACE1 levels became elevated in parallel with amyloid burden in each APP transgenic, starting early in 5XFAD and late in Tg2576. The increase in BACE1 protein occurred without any change in BACE1 mRNA level, indicating a posttranscriptional mechanism. In APP transgenic and AD brains, high BACE1 levels were observed in an annulus around A␤42-positive plaque cores and colocalized with neuronal proteins. These results demonstrate that amyloid plaques induce BACE1 in surrounding neurons at early stages of pathology before neuron death occurs. We conclude that BACE1 elevation is most likely triggered by the amyloid pathway and may drive a positive-feedback loop in AD.

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

“…However, important distinctions between the two fragments could exist regarding their neuronal production and secretion sites, which in turn would determine their sites of biological activity. BACE1 is predominantly localized in endosomes of the soma and the presynaptic terminal (4,17,30,52), although ADAM8 is likely found on the plasma membrane. We determined that BACE1 and CHL1 co-localize in growth cones and terminals of hippocampal mossy fibers and OSN axons (Figs.…”

“…dentate gyrus granule cells, which project axons (mossy fibers) to CA3 pyramidal neurons. Importantly, mossy fiber terminals exhibit robust expression of BACE1 (17,30).…”

APP mouse models for Alzheimer's disease preclinical studies

“…Although specific details of amyloid pathology such as plaque age of onset, size and regional distribution, and Aβ species content vary depending on the line, APP‐overexpressing mice recapitulate aspects of cerebral Aβ accumulation, including production and deposition of Aβ and associated neuroinflammation (microgliosis and astrogliosis). In some cases, downstream pathologic consequences of Aβ deposition in overexpressing mice, such as tau hyperphosphorylation, formation of dystrophic neurites, loss of synaptic markers, and the accumulation of BACE1 (Zhao et al , 2007), appear similar to those observed in AD. Other effects of Aβ deposition in overexpressing mice may also be relevant to AD.…”

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

“…These behavioral deficits are observed concomitant with the onset of hippocampal CA1 synaptic dysfunctions such as reduced basal transmission and long-term potentiation (LTP: a synaptic plasticity model for learning and memory) (Kimura and Ohno, 2009). Furthermore, 5XFAD mice begin to exhibit elevations in expression levels of the b-secretase (b-site APP cleaving enzyme 1: BACE1), which is responsible for initiating the production of Ab, at 6-9 months of age (Devi and Ohno, 2010b;Ohno et al, 2007;Zhang et al, 2009;Zhao et al, 2007), as observed in sporadic AD brains (Fukumoto et al, 2002;Li et al, 2004;Yang et al, 2003). To rigorously test the therapeutic potential of 7,8-DHF, we used the advanced stage of 5XFAD transgenic mice (12-15 months of age) that is more relevant to clinic AD cases manifesting robust amyloidosis, BACE1 elevations, BDNF-TrkB dysfunction, and profound memory impairments.…”