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Increased Alzheimer’s Risk in Women Due to Proteins?

Gender-specific differences between the levels and structures of proteins present in the white matter and the mitochondria of the brains of men and women suffering from dementia have been revealed for the first time in a study published in the open access journal Molecular Brain.

While previous studies have shown that women exhibit higher risk of dementia than men, the underlying mechanisms of this gender difference have remained elusive. The findings by researchers from Nanyang Technological University, Singapore may advance our understanding of the higher risk of dementia that has been observed in women compared to men, which the researchers suggest could lead to the development of new drugs for dementia treatment.

Associate Professor Sze Siu Kwan one of the co-authors of the study said: “The number of dementia patients is projected to triple by 2050 and there is an urgent need to identify key mechanisms of how dementia develops. Our findings and further study could have direct implications for our knowledge about the progression of dementia that could lead to the development of drugs for treatment of dementia.”

The researchers used proteomics – the large-scale study of proteins, including their variations and changes – to analyze the proteins present in post-mortem brain tissues from five male and five female dementia patients and ten healthy controls. The researchers wanted to identify changes in structure and function of the proteins present in the white matter and the mitochondria of the temporal lobe – the part of the brain involved in visual memory and the understanding of language. Proteomics is an unbiased approach as, rather than testing a set of pre-defined, specific proteins, it allowed the researchers to look at thousands of proteins to identify changes associated with dementia.

Degenerative Protein Modifications (DPMs) are changes to proteins that are thought to cause the loss of protein function, similar to the way that steel loses strength when rusting. The protein shown to be most affected by these DPMs in the brains of dementia patients in this study is Myelin Basic Protein (MBP) which is important for the production of a protective myelin layer around the axons of nerve cells. Axons are part of the brain’s white matter which transmits signals between different parts of the brain. A process called myelation provides an electrically insulating layer around axons, similar to the insulation around an electrical wire. Damage to that insulating layer can stop electrical impulses from being conducted properly, disrupting communication between different parts of the brain. DPMs that are thought to increase the dysfunction of MBP were found to be more pronounced in women than in men. Sze Siu Kwan said: “As DPMs are likely to critically influence protein function and activity in the central nervous system they can be novel drug targets for treatment of dementia.”

Image shows an old lady.

“The findings of this study indicate that proteomics can detect differences between male and female dementia patients on a molecular level which cannot be detected by standard approaches,” Xavier Gallart-Palau says. Image is for illustrative purposes only.

The researchers detected changes in the presence of certain proteins in the mitochondria of patients suffering from dementia that indicate mitochondrial dysfunction. Mitochondria are responsible for creating energy needed to sustain proper cell function, including brain cell function. Mitochondrial dysfunction can lead to cell injury or even cell death. As with changes to other proteins, disturbance to the proteins in the mitochondria was observed to be more pronounced in women than in men.

Xavier Gallart-Palau, the first author of the paper said: “The findings of this study indicate that proteomics can detect differences between male and female dementia patients on a molecular level which cannot be detected by standard approaches.”

The findings also provide new insight into the molecular basis of increased risk and severity in women suffering from dementia. They may be a step towards future clinical interventions targeted at reducing dementia risk in both men and women.

About this Alzheimer’s disease research

Source: Anne Korn – BioMed Central
Image Source: The image is in the public domain.
Original Research: Full open access research for “Gender differences in white matter pathology and mitochondrial dysfunction in Alzheimer’s disease with cerebrovascular disease” by Xavier Gallart-Palau, Benjamin S. T. Lee, Sunil S. Adav, Jingru Qian, Aida Serra, Jung Eun Park, Mitchell K. P. Lai, Christopher P. Chen, Raj N. Kalaria and Siu Kwan Sze in Molecular Brain. Published online March 17 2016 doi:10.1186/s13041-016-0205-7


Abstract

Gender differences in white matter pathology and mitochondrial dysfunction in Alzheimer’s disease with cerebrovascular disease

Background
Dementia risk in women is higher than in men, but the molecular neuropathology of this gender difference remains poorly defined. In this study, we used unbiased, discovery-driven quantitative proteomics to assess the molecular basis of gender influences on risk of Alzheimer’s disease with cerebrovascular disease (AD + CVD).

Results
We detected modulation of several redox proteins in the temporal lobe of AD + CVD subjects, and we observed sex-specific alterations in the white matter (WM) and mitochondria proteomes of female patients. Functional proteomic analysis of AD + CVD brain tissues revealed increased citrullination of arginine and deamidation of glutamine residues of myelin basic protein (MBP) in female which impaired degradation of degenerated MBP and resulted in accumulation of non-functional MBP in WM. Female patients also displayed down-regulation of ATP sub-units and cytochromes, suggesting increased severity of mitochondria impairment in women.

Conclusions
Our study demonstrates that gender-linked modulation of white matter and mitochondria proteomes influences neuropathology of the temporal lobe in AD + CVD.

“Gender differences in white matter pathology and mitochondrial dysfunction in Alzheimer’s disease with cerebrovascular disease” by Xavier Gallart-Palau, Benjamin S. T. Lee, Sunil S. Adav, Jingru Qian,
Aida Serra, Jung Eun Park, Mitchell K. P. Lai, Christopher P. Chen, Raj N. Kalaria and Siu Kwan Sze in Molecular Brain. Published online March 17 2016 doi:10.1186/s13041-016-0205-7

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