Impaired proteins and gender differences in dementia

In support of Brain Awareness Week, we’re highlighting some of the amazing benefits of brain research and showcasing the progress being made by researchers around the world (learn more here). Molecular Brain today publishes research exploring the molecular basis of gender differences in dementia, focusing on Alzheimer’s with cerebrovascular disease. Co-author Xavier Gallart-Palau explains more in this guest blog.

The silent epidemic

I can still remember the moment my grandmother was no longer able to recognize my face. When I was young she taught me how to cycle, she read me books and cared for me when I fell over. Had the affection of these memories also been forgotten? Unfortunately we will never know as she was very soon unable to explain what was in her mind. This devastating experience encouraged me to research the basis of temporal dementia.

Dementia is considered the ‘silent epidemic’ of the 21st century which is currently affecting almost 50 million people worldwide. Around the world, a new case of dementia is diagnosed every 3.2 seconds on average, where Alzheimer’s disease is the major contributor to this global epidemic.

According to recent reports from the American Alzheimer’s Association and the Australian Institute of Health and Welfare, two thirds of patients diagnosed with Alzheimer’s are women. This ratio increases to 75% among those aged over 80 years.

Investigating the molecular basis of dementia

The molecular basis of gender differences on the prevalence of dementia remained understudied for a long time.

The molecular basis of gender differences on the prevalence of dementia remained understudied for a long time. If we want to beat our adversary we need to know it in depth, therefore, the development of effective new therapies for patients with dementia will require a better understanding of the neurodegenerative pathology at the molecular level.

Although we are still at a very early stage of neurodegenerative research there is room for hope as not all that we find is bad news. Research in animal models suggests that the effects of aging on brain neurons and cognitive function are likely reversible if we acquire a better understanding of the molecular basis of neurodegeneration.

Using proteomics to identify gender differences in Alzheimer’s

A good field to decipher the molecular basis of neurodegeneration from an unbiased discovery-driven approach is proteomics, the large-scale study of proteins. This high throughput technological field allows characterization of level and composition of thousands of proteins from post-mortem brain samples.

A new study directed by Professor Sze Siu Kwan and published in Molecular Brain adopted discovery-driven proteomics to decipher the molecular basis of gender differences in Alzheimer’s with cerebrovascular disease (CVD), the most common dementia-associated neurodegenerative disease in the elderly.

After global evaluation of over 1500 proteins from post-mortem brain tissues of men, women with dementia and age-matched controls, we found gender-associated regulation of myelin and mitochondrial proteins.

In this study, after global evaluation of over 1500 proteins from post-mortem brain tissues of men, women with dementia and age-matched controls, we found gender-associated regulation of myelin and mitochondrial proteins.

Altered proteins

Higher damage of white matter was found in women with dementia despite the fact that the levels of several myelin proteins were also higher in women. This fact indicates an incorrect remyelination response in that group. Impaired remyelination might be associated with higher occurrence of degenerative protein modifications in the key white matter protein, also known as myelin basic protein (MBP).

Degenerative protein modifications alter the charge and molecular composition of proteins. As a consequence, this impairs their structure and function. MBP was found to be highly affected by the degenerative protein modifications deamidation and citrullination in the temporal lobe of Alzheimer’s with CVD female patients.

Higher deamidation of MBP in women with dementia promoted accumulation of dysfunctional MBP leading to an impaired remyelination response compared to men with dementia. This fact might have direct implications on the cognitive manifestations of dementia.

Mitochondria, the organelles responsible for supplying energy to brain cells, were also more impaired in women with dementia than in men. This suggests higher vulnerability of neurons to cell death in that group.

The future of dementia treatment

Degenerative protein modifications are ‘drugable’ targets that hold promise for the treatment of dementia if we acquire further understanding of their impact on healthy and dysfunctional proteins.

Degenerative protein modifications are ‘drugable’ targets that hold promise for the treatment of dementia if we acquire further understanding of their impact on healthy and dysfunctional proteins. As it was found in this study, degenerative protein modifications seem to play a crucial role in the molecular basis of gender differences in Alzheimer’s with CVD.

Similarly, the temporal and functional relationships established between white matter disease and mitochondria dysfunction in Alzheimer’s with CVD seem to act as a crucial event of the neurodegenerative process and requires further attention in future research.


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