Summary: Researchers have identified the key mechanism that may be responsible for the cognitive decline observed in the natural aging process. They found that the mis-regulation of a brain protein known as CaMKII, vital for memory and learning, is linked to this decline.
Aging decreases S-nitrosylation, a process modifying specific brain proteins, including CaMKII, thereby impairing memory and learning ability. The findings point towards potential pharmacological strategies to normalize protein nitrosylation, potentially combating age-related cognitive decline.
Researchers have found that the mis-regulation of a brain protein called CaMKII could be the central mechanism behind cognitive decline related to normal aging.
The study revealed that normal aging reduces the process of S-nitrosylation, modifying specific brain proteins, which impairs memory and learning ability.
These findings open potential avenues to develop drugs or other therapeutic interventions that can normalize the nitrosylation of CaMKII, possibly staving off normal cognitive decline.
Source: University of Colorado
Scientists at the University of Colorado Anschutz Medical Campus have discovered what they believe to be the central mechanism behind cognitive decline associated with normal aging.
“The mechanism involves the mis-regulation of a brain protein known as CaMKII which is crucial for memory and learning,” said the study’s co-senior author Ulli Bayer, PhD, professor of pharmacology at the University of Colorado School of Medicine. “This study directly suggests specific pharmacological treatment strategies.”
The study was published today in the journal `Science Signaling.’
Researchers using mouse models found that altering the CaMKII brain protein caused similar cognitive effects as those that happen through normal aging.
Bayer said that aging in mice and humans both decrease a process known as S-nitrosylation, the modification of a specific brain proteins including CaMKII.
“The current study now shows a decrease in this modification of CaMKII is sufficient to cause impairments in synaptic plasticity and in memory that are similar in aging,” Bayer said.
Normal aging reduces the amount of nitric oxide in the body. That in turn reduces nitrosylation which reduces memory and learning ability, the study said.
Bayer said the new research opens the way toward developing drugs and other therapeutic interventions that could normalize the nitrosylation of the protein. He said that holds out the possibility of treating or staving off normal cognitive decline for an unknown period of time.
He pointed out that this would only work in normal age-related cognitive decline, not the decline seen in Alzheimer’s disease and dementia.
“We know this protein can be targeted,” Bayer said. “And we think it could be done pharmacologically. That is the next logical step.”
Decreased nitrosylation of CaMKII causes aging-associated impairments in memory and synaptic plasticity in mice
CaMKII has molecular memory functions because transient calcium ion stimuli can induce long-lasting increases in its synaptic localization and calcium ion–independent (autonomous) activity, thereby leaving memory traces of calcium ion stimuli beyond their duration.
The synaptic effects of two mechanisms that induce CaMKII autonomy are well studied: autophosphorylation at threonine-286 and binding to GluN2B. Here, we examined the neuronal functions of additional autonomy mechanisms: nitrosylation and oxidation of the CaMKII regulatory domain.
We generated a knock-in mouse line with mutations that render the CaMKII regulatory domain nitrosylation/oxidation-incompetent, CaMKIIΔSNO, and found that it had deficits in memory and synaptic plasticity that were similar to those in aged wild-type mice.
In addition, similar to aged wild-type mice, in which CaMKII was hyponitrosylated, but unlike mice with impairments of other CaMKII autonomy mechanisms, CaMKIIΔSNO mice showed reduced long-term potentiation (LTP) when induced by theta-burst stimulation but not high-frequency stimulation (HFS). As in aged wild-type mice, the HFS-LTP in the young adult CaMKIIΔSNO mice required L-type voltage-gated calcium ion channels.
The effects in aged mice were likely caused by the loss of nitrosylation because no decline in CaMKII oxidation was detected.
In hippocampal neurons, nitrosylation of CaMKII induced its accumulation at synapses under basal conditions in a manner mediated by GluN2B binding, like after LTP stimuli. However, LTP-induced synaptic CaMKII accumulation did not require nitrosylation.
Thus, an aging-associated decrease in CaMKII nitrosylation may cause impairments by chronic synaptic effects, such as the decrease in basal synaptic CaMKII.