Plasticity—It’s Not Just for Neurons
In contrast to Aβ’s acute effects on blood flow, some studies show longer-term effects on vascular remodeling. Michael Mullan of the Roskamp Institute in Sarasota, Florida, is studying anti-angiogenic effects of Aβ. Mullan reported that transgenic APPSw mice show decreased cerebral blood flow at all ages, and decreased vascular density early in life. Cultured aorta pieces from these mice showed impaired angiogenesis (Paris et al, 2004). Mullan has described direct anti-angiogenic effects of Aβ peptides in both in-vitro and in-vivo assays, including inhibition of tumor growth (Paris et al., 2004). He found that soluble Aβ aggregates were potently anti-angiogenic, while fibrillar Aβ40 peptides had no effect. The implication is that oligomeric Aβ aggregates in effect reduce blood flow in the brain.
A separate model of angiogenesis, hypoxic adaptation, revealed that aging rats lose the ability to remodel their vasculature in response to low oxygen, according to Joseph LaManna of Case Western Reserve University in Cleveland, Ohio. LaManna stressed rats by placing them in 10 percent oxygen, a level equivalent to an elevation of 18,000 feet. (People in the Andes and Tibet live at 14,000 feet.) After 3 weeks, the capillary density in brain increased by about 80 percent, revealing a plasticity that came as a “shock and a surprise” to LaManna. When the rats were re-oxygenated, the number of their capillaries returned to the original level within 3 weeks. In old rats, on the other hand, capillary density did not change under low-oxygen conditions.
The capillary increase is mediated by the action of hypoxia-inducible transcription factor (HIF1), a normally short-lived protein whose degradation slows when oxygen levels fall. As HIF1 accumulates, it activates genes that trigger angiogenesis, most prominently vascular endothelial growth factor. In old rats subjected to hypoxia, HIF1 did not accumulate, nor were hypoxia-induced genes activated (Dore-Duffy and LaManna, 2007). HIF1 is expressed and can be pharmacologically activated, but the brain appears to have lost its oxygen-sensing capability, said LaManna.
Because atherosclerosis and AD share many features, could research on new treatments for heart disease benefit AD? That is a question posed by Samuel Wright, Merck’s head of cardiovascular and atherosclerosis research. Both diseases are huge public health problems that progress silently over decades and share similar risk factors. Both involve cholesterol-containing plaques of complex composition, both feature competing concepts of pathology, and for both diseases, homocysteine levels are a strong independent risk factor.
The cholesterol connection led to clinical trials of statins, which have not yet shown unequivocal positive results (see ARF related news story; Riekse et al., 2006; Sparks et al., 2006). The next big thing for heart disease, Wright opined, will be treatments for metabolic syndrome, a constellation of risk factors that occur in one person and appear to mark an underlying metabolic dysfunction. They include abdominal obesity, high blood pressure, insulin resistance, dyslipidemia, and a high risk for cardiovascular disease. Forty percent of Americans older than 60 fit the definition of metabolic syndrome, which is associated with an increased risk of age-related cognitive decline (see ARF related news story).
Merck and other companies are working on potential treatments for metabolic syndrome that target the production of cortisol by the enzyme 11-βhydroxy steroid dehydrogenase (11-βHSD). This enzyme regulates local transformation of inactive cortisone to cortisol in adipose and other tissues, thereby raising intracellular glucocorticoid levels. An inhibitor of HSD developed by Merck reverses the features of metabolic syndrome and atherosclerosis in mice (Hermanowski-Vosatka et al., 2005). Some recent evidence for the importance of HSD in cognitive decline comes from studies showing that aged HSD knockout mice maintain better hippocampal function than aged wild-type mice (Yau et al., 2007..The aged knockouts perform better in the Morris water maze and maintain a youthful capacity for synaptic potentiation.
Consistent with the HSD knockout results, Wright showed that Merck’s HSD inhibitor improved cognitive function in aged Balb C mice, as measured by a novel object recognition test. By 14 months of age, mice had largely lost their ability to distinguish between previously encountered objects and new ones. However, if the mice received an HSD inhibitor in their food for 3 months or more before the recognition test, the response to novel objects improved and more closely resembled that of younger animals.
Merck is developing an HSD inhibitor for cardiovascular disease. Opportunities to expand testing of this and other novel therapeutics to the arena of cognitive decline may depend on the discovery of biomarkers, Wright said.
Ajay Verma, also of Merck, ended the symposium with a talk on a new kind of biomarker of vascular function, a method for non-invasively measuring cerebral blood flow in the clinic. He described transcranial Doppler of the circle of Willis, an arterial structure at the base of the brain, whose branches feed into areas important for cognition. While readings show individual variation, Merck has made a normative database of more than 1,000 people. The scientists can take readings from 18 vessels and compare them to the database to get what Verma called a “footprint” of vascular health. So far, the researchers see dramatic differences in most vessels in AD versus controls. The next step is to examine patients who are using acetylcholinesterase inhibitors, to see if this relatively simple, non-invasive procedure registers any cholinergic-mediated changes in blood flow.
Just as neurons do not stand alone, this symposium served as a reminder that neither should researchers be segregated based on their affinity for studying neurons or the vasculature. Between sessions, attendees were overheard hatching new collaborations—a breakdown of the blood-brain research barrier that bodes well for a full understanding of Alzheimer disease.—Pat McCaffrey.