9 July 2010. Much of our understanding of Alzheimer disease has come from studies of small, scampering creatures, namely mice, that normally age without racking up plaques or tangles. But in comparison to people, rodents have but a tiny cortex, which is the area that is most extensively ravaged by AD pathology. For research on age-related decline that hits closer to home, taxonomically and anatomically, check out two recent studies of rhesus monkeys in the Journal of Neuroscience. In the June 2 issue, researchers led by John Morrison, Mount Sinai School of Medicine, New York, attribute age-associated memory failure in these primates to selective loss of synapses thought to be important for learning new information. And in the June 9 issue, a study by Sterling Johnson, University of Wisconsin, Madison, and colleagues suggests that calorie restriction—which promotes longevity in many species—slows two known markers of aging: iron buildup in the basal ganglia and waning motor performance.
The studies do not directly address AD, but focus on brain changes that accompany aging. Morrison’s paper, for example, homes in on synaptic alterations. Live imaging of rodent neocortex has shown that small, thin spines are highly plastic and dynamic compared with larger, mushroom spines, which hang around much longer. This led scientists to believe thin spines might be key for learning, while the large, stable ones may function more in long-term memory, which is less sensitive to aging, Morrison told ARF. In support of this idea, it was the smaller spines in particular that fizzled with age but revived with estrogen treatment in his lab’s recent studies of rhesus monkeys (Hao et al., 2007; Hao et al., 2006). Despite questionable neuroprotective benefits in people (see ARF related news story), estrogen does stave off memory loss in aging monkeys.
In the current study, first author Dani Dumitriu and colleagues put young and old rhesus monkeys through object recognition memory tests, and analyzed their brains soon after. Using quantitative electron microscopy to examine postmortem tissue, the researchers looked for synaptic changes in layer III prefrontal cortex—the same region (Brodmann area 46) that had previously responded to estrogen treatment. In the present study, poorer task performance in older monkeys did not associate with mushroom spine size or density, but showed “an incredibly high correlation with the size of the smaller class of synapses,” Morrison said. The number of small spines were “highly predictive of the animal’s cognitive decline and ability to learn the new task,” said Morrison, noting that the spine loss did not correlate with memory performance once the monkeys had learned the delayed non-matching-to-sample task.
Morrison thinks the findings could be relevant to AD. “We know it’s the same brain areas and the same neurons that are vulnerable to synapse loss in Alzheimer disease,” he told ARF. “What we don’t know is whether the synapse loss that occurs with aging leaves the neuron vulnerable to AD, or whether they’re two independent processes.” Still, Morrison believes that “if you can protect neurons from synapse loss, you can retain their health and perhaps protect them from AD as well.”
Whether this is true remains to be seen. For now, the findings “provide a very specific basis for the cognitive decline that occurs naturally with aging, because they point to a certain subset of synapses—the most plastic ones that we think are particularly important for how the prefrontal cortex learns,” Morrison said. Understanding the molecular and structural features that distinguish subsets of spines—presumably enabling them to process information and respond to inputs differently—could lead to new ways to protect the highly vulnerable small synapses, he said.
Protection from aging was also a prime focus of the study by Johnson and colleagues, whose findings offer up several markers for gauging how well a common life-extending regimen works. Last year, Richard Weindruch, also at the University of Wisconsin and coauthor on the current paper, showed that slashing calories not only gave rhesus monkeys a longer life, but also made them less prone to age-related disease (Colman et al., 2009 and ARF related news story). Johnson, who uses live imaging to track brain changes during AD, figured that “if calorie restriction was good for the brain, we ought to be able to see some indication of that.” Applying his human computational neuroscience expertise toward Weindruch’s ongoing primate study, Johnson found that the dieting monkeys had less brain atrophy (see Bendlin et al., 2010 and Willette et al., 2010).
In the present study, first author Erik Kastman and colleagues looked to see whether calorie restriction affects two additional signatures of aging—iron accumulation and poor motor performance. They found iron levels rose more slowly in older dieting monkeys, suggesting their brains were biologically younger than those of animals eating without restriction. Iron collects most in the basal ganglia regions that regulate motor abilities, and the researchers found that fine motor skills during a food retrieval task were better in calorie-restricted monkeys compared with those on normal chow.
The researchers will follow the monkeys longitudinally to see if consuming fewer calories continues to slow the rate of age-related brain atrophy, as well as affect the two newly identified parameters, Johnson told ARF.
Again, the connection with AD was unclear in the current study, though others have reported lower brain amyloid in AD transgenic mice on a calorie-restricted diet (Wang et al., 2005). As for primates, certain species may actually accumulate amyloid and tau pathology with age (Rosen et al., 2008 and ARF related news story). That said, research in monkeys and chimps is much tougher than in rodents. It takes time—and money—to breed primates and let them grow old enough to develop pathology and cognitive dysfunction, Morrison said. In the meantime, he thinks learning more about aging biomarkers could guide future research in primates, perhaps even people, by providing more precise targets to study. “If we knew that the vulnerable class of synapses had, let’s say, one receptor that the very stable synapses don’t have, we might be able to start doing imaging on a receptor-based level in humans,” Morrison speculated.—Esther Landhuis.
Dumitriu D, Hao J, Hara Y, Kaufmann J, Janssen WG, Lou W, Rapp PR, Morrison JH. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci. 2010 Jun 2;30(22):7507-15. Abstract
Kastman EK, Willette AA, Coe CL, Bendlin BB, Kosmatka KJ, McLaren DG, Xu G, Canu E, Field AS, Alexander AL, Voytko ML, Beasley TM, Colman RJ, Weindruch RH, Johnson SC. A calorie-restricted diet decreases brain iron accumulation and preserves motor performance in old rhesus monkeys. J Neurosci. 2010 Jun 9;30(23):7940-7. Abstract