Researchers have discovered key details of how stroke or traumatic brain injury can trigger Alzheimer’s disease (AD) by enhancing formation of brain-clogging amyloid plaques. Their experiments established that “executioner” enzymes that kill brain cells during stroke or head trauma also interfere with the normal disposal of an enzyme that helps generate plaque. This interference increases the level of the enzyme in brain cells, they found.
The researchers, led by Giuseppina Tesco and Rudolph Tanzi of Massachusetts General Hospital, reported their findings in the June 7, 2007, issue of the journal Neuron, published by Cell Press.
The researchers sought to understand the mechanism by which stroke or brain injury causes the increase of an enzyme called BACE in the brain. BACE is a protein-cleaving enzyme that snips apart a brain protein called amyloid precursor protein to form a shorter protein called A beta peptide. It is this A beta peptide that is the building block for the amyloid plaques that are a hallmark of AD.
The researchers discovered that particular enzymes produced during brain injury, called caspases, somehow also enable BACE to linger in brain cells. Caspases are so-called “executioner” enzymes that destroy brain cells such as those damaged by oxygen deprivation during stroke.
In further exploring the link between caspase activation and higher BACE levels, the researchers found that one of the proteins snipped apart by caspase activity is GGA3. This protein is an adaptor protein necessary for shepherding BACE to the cell’s garbage disposal machinery, the lysosome. The researchers found that caspase snipping of GGA3 not only eliminates GGA3's ability to tag BACE for destruction but that the resulting fragments of GGA3 actively interfere with BACE disposal.
To test the role of GGA3, the researchers “silenced” activity of the GGA3 gene in brain cells, finding that the silencing caused increased levels of BACE and the amyloid proteins.
And they found that inducing strokes in rats caused GGA3 to be degraded and BACE levels to increase. Finally, when they analyzed brain tissue from people with AD, they found decreases in GGA3 levels that were inversely correlated with increases in BACE.
The researchers pointed out that studies have shown that “individuals with AD and cerebrovascular pathologies show greater cognitive impairment than those exhibiting either pathology alone. These studies indicate that there is an additive or synergistic interaction between AD and cerebrovascular pathologies.”
“Furthermore, evidence is accumulating that stroke and transient ischemic attacks significantly increase the risk of AD in elderly individuals…. Thus, stroke may represent either a precipitating or a triggering event in AD,” they wrote.
In summary, wrote Tesco, Tanzi, and their colleagues, other researchers’ studies, “taken together with our current data, suggest that accumulative insults to the brain over one’s lifetime would progressively increase risk for AD by elevating cerebral A beta accumulation via BACE stabilization owing to caspase-mediated depletion of GGA3.”
The researchers include Giuseppina Tesco, Young Ho Koh, Eugene L. Kang, Andrew N. Cameron, Shinjita Das, Miguel Sena-Esteves, Mikko Hiltunen, and Rudolph E. Tanzi of Massachusetts General Hospital in Charlestown, MA; Shao-Hua Yang and James W. Simpkins of University of North Texas Health Science Center in Fort Worth, TX; Zhenyu Zhong and Yong Shen of Sun Health Research Institute in Sun City, AZ.
This work is supported by NIH grants 1K12MH069281-01 (to G.T.) and 1R01AG025952-01A2 (to G.T.), NIMH grant 1R37MH60009 (to R.E.T.), American Health Assistance Foundation (to R.E.T.), Cure Alzheimer’s Fund (to R.E.T.), and the John French Douglas Foundation Fellowship (to Y.H.K.).
Tesco et al.: “Depletion of GGA3 Stabilizes BACE and Enhances b-Secretase Activity.” Neuron 54, 721–737, June 7, 2007. DOI 10.1016/j.neuron.2007.05.012. www.neuron.org.