New research not only helps to explain why age is such a large risk factor for Alzheimer’s, but why higher brain circuits regulating cognition are so vulnerable to degeneration while the sensory cortex remains unaffected.
As we age, highly evolved brain circuits become susceptible to molecular changes that can lead to neurofibrillary tangles—a hallmark of Alzheimer’s disease.
“We hope that understanding the key molecular alterations that occur with advancing age can provide new strategies for disease prevention,” says Amy F.T. Arnsten, professor of neurobiology at Yale University and one of the senior authors of the study that is published online in the Proceedings of the National Academy of Sciences.
Neurofibrillary tangles are made from a protein called tau, which becomes sticky and clumps together when modified in a process called phosphorylation. The new study shows that phosphorylated tau collects in neurons in higher brain circuits of the aging primate brain, but does not accumulate in neurons of the sensory cortex.
Phosphorylated tau collects in and near the excitatory connections called synapses where neurons communicate and can spread between cells in higher brain circuits.
Researchers found clues about what causes tau to become phosphorylated with advancing age and uncovered age-related changes in the molecular signals that control the strength of higher cortical connections.
In young brains, an enzyme called phosphodiesterase PDE4A sits near the synapse where it inhibits a chemical “vicious cycle” that disconnects higher brain circuits when we are in danger, switching control of behavior to more primitive brain areas.
PDE4A is lost in the aged prefrontal association cortex, unleashing a chemical cascade of events that increase the phosphorylation of tau. This process may be amplified in humans, where high order cortical neurons have even more excitatory connections, leading to tangle formation and ultimately cell death.
“This insight into one pathway by which tau may influence the onset and progression of Alzheimer’s disease takes us a step closer to unraveling this complex and devastating disorder,” says Molly Wagster of the National Institutes of Health.
The new study may also help to explain why head injury is a risk factor for Alzheimer’s, as it may also increase the activity of the chemical cycle.
“Now that we begin to see what makes neurons vulnerable, we may be able to protect cells with treatments that mimic the protective effects of PDE4A,” Arnsten says.
The National Institute on Aging, the National Institutes of Health, and the Kavli Neuroscience Institute at Yale supported the work.