28 November 2006. Two new papers reveal how environmental influences can directly affect the activity of the APP-processing enzymes β-secretase (BACE1) and γ-secretase. The studies, which link hypoxia to an increase in BACE expression and activity, and β-adrenergic stimulation to increased γ-secretase activity, could explain epidemiological data linking stroke and vascular insufficiency to Alzheimer disease. In addition, the studies offer some intriguing possibilities for the pharmacological modulation of Aβ production.
The first paper, from Weihong Song and colleagues at the University of British Columbia in Vancouver, deals with β-secretase (BACE1) gene expression and Aβ production under hypoxic conditions in cultured cells and in an AD mouse model. The work, published November 22 in the PNAS Early Edition, shows that chronic hypoxia elevates BACE1 in vitro and in vivo, and exacerbates amyloid pathology and memory deficits in an AD mouse model.
The expression of BACE1 is tightly controlled, and increases with age, in Alzheimer disease, and as Robert Vassar and colleagues showed recently, with energy depletion in the brain (Veliquette et al., 2005 and ARF Madrid coverage). To examine the effects of low oxygen on BACE1 gene expression, first author Xiulian Sun first looked at the regulation of the BACE1 gene, or the BACE1 promoter linked to a reporter gene, in SH-SY5Y cells under low oxygen (2 percent) conditions. Sun found that BACE transcription was elevated, and that the induction involved binding of the classic hypoxia-induced transcription factor HIF1 to a specific site in the BACE1 promoter. In SH-SY5Y cells, hypoxia resulted in a roughly threefold increase in BACE1 protein, and a modest increase in Aβ40 and Aβ42 levels (25 and 50 percent, respectively).
To measure the effects of hypoxia in vivo, the authors exposed APP23 transgenic mice to low oxygen conditions (8 percent vs. the normal atmospheric level of 21 percent) for 16 hours a day. After one month, the mice showed a 50 percent increase in the C99 BACE cleavage fragment of APP, a threefold increase in Aβ40, and an almost twofold increase in Aβ42. Plaque number was elevated by about 50 percent, and the mice showed worse performance in the Morris water maze compared to control mice kept in room air.
Hypoxia-driven β-secretase activity and the subsequent increase in APP processing might explain how stroke and other vascular risk factors contribute to the risk of AD. Furthermore, the finding suggests a strategy for reducing amyloid deposition. “Our study suggests that enhancing oxygen supply by improving cerebral perfusion or by using vasodilators may have pharmaceutical potential for treating cognitive impairments, thereby benefiting AD patients,” the authors write.
The second paper, which appeared in Nature Medicine online on November 19, links environmental stress, which activates the β-adrenergic response, to Aβ production through elevated γ-secretase activity. Gang Pei and colleagues at the Shanghai Institutes for Biological Sciences in China show that agonists of the β2-adrenergic receptor (β2-AR) increase γ-secretase activity, both in vitro and in vivo, and Aβ production, while a β2-AR antagonist downregulated the amyloidogenic pathway.
The natural ligands of the β2-AR—epinephrine and norepinephrine—mediate the body’s response to stress. To look at the possible role of this pathway in amyloid production, first authors Yanxiang Ni and Xiaohui Zhao pharmacologically stimulated HEK293 cells transfected with an APPswe construct. They found the β2-AR agonist isoproterenol increased Aβ40 and Aβ42 secretion. In a series of cell-based experiments, they established that the stimulation was due to increased γ-secretase activity. More specifically, the increased activity resulted from the co-internalization of γ-secretase with the β2-AR. By using coimmunoprecipitation methods, the authors showed that the β2-AR and presenilin protein appear to be in direct physical contact on the cell surface. Binding of β2-AR agonists triggered internalization of the receptor plus the presenilin/γ-secretase complex, followed by the trafficking of the γ-secretase to a late endosome/lysosome compartment where it increased activity and boosted Aβ production.
In vivo, β2-AR agonists also increased Aβ production. In rats, intracerebroventricular injection of norepinephrine increased hippocampal γ-secretase activity and Aβ levels about 1.5 times. Chronic treatment of AD mice (APPswe/PS1 ΔE9) for 30 days with isoproterenol or clenbuterol modestly increased plaque area, while mice treated with a β2-AR antagonist (ICI 118,551) had a decreased plaque load. Of the latter result, the authors write, “As β-AR antagonists are widely used in the treatment of cardiovascular disease, our study proposes another potential therapeutic use for β2-AR antagonists.”
This work comes on the heels of an epidemiological study showing that the β-blockers were one of a few classes of hypertensive drugs that seemed to reduce the risk of AD in long-time users (see ARF related news story). Based on the current work, the benefits of such drugs could be a two-fer if they inhibited γ-secretase activation and kept BACE1 down by increasing blood flow.—Pat McCaffrey.
Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, Song W. Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci U S A. 2006 Nov 22; [Epub ahead of print] Abstract
Ni Y, Zhao X, Bao G, Zou L, Teng L, Wang Z, Song M, Xiong J, Bai Y, Pei G. Activation of beta(2)-adrenergic receptor stimulates gamma-secretase activity and accelerates amyloid plaque formation.
Nat Med. 2006 Nov 19; [Epub ahead of print] Abstract