The Synapses of Some Individuals Appear Resilient to Age-Related Protein Aggregation

We all, to some degree, accumulate harmful protein aggregates in the brain with age, but only some people develop severe neurodegenerative disease as a result. The rest of the population remains mildly impaired. Why is this? Some have suggested that Alzheimer's disease and the like are to some degree lifestyle conditions, aggravated by the presence of excess visceral fat tissue and the abnormal metabolism that results. Alternatively the microbial hypothesis suggests that only some people have sufficient persistent infection by herpesviruses or lyme spirochetes to result in high levels of protein aggregates. Theories of impaired cerebrospinal fluid drainage point to differing levels of structural failure in fluid channels leading from the brain. Researchers here propose another mechanism, in that some people have synapses that are resilient to the harms inflicted by tau aggregation, thought to be the most damaging mechanism in late stage Alzheimer's disease.

People suffering from Alzheimer's disease (AD) develop a buildup of two proteins that impair communications between nerve cells in the brain - plaques made of amyloid beta proteins and neurofibrillary tangles made of tau proteins. Intriguingly, not all people with those signs of Alzheimer's show any cognitive decline during their lifetime. The question became, what sets these people apart from those with the same plaques and tangles that develop the signature dementia?

"In previous studies, we found that while the non-demented people with Alzheimer's neuropathology had amyloid plaques and neurofibrillary tangles just like the demented people did, the toxic amyloid beta and tau proteins did not accumulate at synapses, the point of communication between nerve cells. When nerve cells can't communicate because of the buildup of these toxic proteins that disrupt synapse, thought and memory become impaired. The next key question was then what makes the synapse of these resilient individuals capable of rejecting the dysfunctional binding of amyloid beta and tau?"

The researchers analyzed the protein composition of synapses isolated from frozen brain tissue donated by people who had participated in brain aging studies. The participants were divided into three groups - those with Alzheimer's dementia, those with Alzheimer's brain features but no signs of dementia, and those without any evidence of Alzheimer's. The results showed that resilient individuals had a unique synaptic protein signature that set them apart from both demented AD patients and normal subjects with no AD pathology. "We don't yet fully understand the exact mechanisms responsible for this protection. Understanding such protective biological processes could reveal new targets for developing effective Alzheimer's treatments."



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