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Molecular mechanisms

What causes increased cAMP signaling with advancing age?

The phosphodiesterase PDE4A is anchored by DISC1 to the spine apparatus where it is positioned to regulate feed-forward cAMP-Ca2+ signaling. In the aged cortex, PDE4A is lost from dendritic spines, leading to an increase in Ca2+-cAMP signaling in PFC with advancing age.

Increased vulnerability for degeneration

Neurofibrillary tangles are a pathological marker of Alzheimer’s Disease. They occur in pyramidal cells in the association cortex, but not in the primary sensory cortices. Neurofibrillary tangles arise from the hyperphosphorylation of tau. We have found that increased Ca2+-cAMP signaling in the aged PFC leads to increased phosphorylation of tau, which accumulates over the spine apparatus, within glutamate-like synapses on spines, and on microtubules in dendrites of pyramidal cells. There is also evidence that phosphorylated tau may traffic in vesicles, perhaps traveling between neurons in pyramidal cell circuits. This may explain why higher cortical circuits that interconnect on spines are so vulnerable to degeneration in the aged human brain. The data may also help to explain why head injury and emotional distress are additional risk factors for degeneration, as they also increase Ca2+-cAMP signaling in PFC.

If you are interested: Lewis DA, Campbell MJ, Terry RD, Morrison JH. Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer's disease: a quantitative study of visual and auditory cortices. J Neurosci. 7:1799-808, 1987. Carlyle et al, in press, PNAS.