Proteomic Clues to Higher Risk of Dementia of Women

    Expect the number of dementia patients to triple by 2050, but don’t expect any cures, not anytime soon. In hopes of learning how to slow dementia, scientists are trying to understand how the condition progresses at the molecular level, where drugs might be effective. For example, scientists based at Nanyang Technological University (NTU) in Singapore have been using proteomics, the large-scale study of proteins, to identify patterns associated with dementia.

    The NTU team, led by Newman Sze Siu Kwan, Ph.D., was particularly interested in using proteomics to understand two well-documented facts about dementia. First, women are known to exhibit higher dementia prevalence and severity than men. Second, dementia and Alzheimer’s disease (AD) have been associated with cerebrovascular disease (CVD) affecting circulation of blood in the brain.

    To explore possible connections, the scientists analyzed the proteins present in postmortem brain tissues from five male and five female dementia patients and 10 healthy controls. The researchers wanted to identify changes in structure and function of the proteins present in the white matter (WM) and the mitochondria of the temporal lobe—the part of the brain involved in visual memory and the understanding of language.

    The scientists presented their results March 17 in the journal Molecular Brain, in an article entitled, “Gender Differences in White Matter Pathology and Mitochondrial Dysfunction in Alzheimer’s Disease with Cerebrovascular Disease.” Their results, the scientists suggested, demonstrate that gender-linked modulation of white matter and mitochondria proteomes influences neuropathology of the temporal lobe in AD + CVD.

    “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,” the article’s authors wrote. “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.”

    The scientists also observed that female patients displayed downregulation of adenosine triphosphate (ATP) subunits and cytochromes. According to the scientists, this suggests that mitochondria impairment is more severe among women.

    The scientists explained their results in terms of degenerative protein modifications (DPMs), which 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 MBP, which is important for the production of a protective myelin layer around the axons of nerve cells.

    A process called myelination 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. “As DPMs are likely to critically influence protein function and activity in the central nervous system,” noted Dr. Siu Kwan Sze, “they can be novel drug targets for treatment of dementia.”

    The study’s results also pointed to the potential role of mitochondrial dysfunction in dementia. 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.

    “In particular, we observed that hyper-citrullination and hyper-deamidation of MBP were prevalent in female dementia patients,” the study emphasized. “Specifically, deamidation of the glutamine residue 82 in the MBP degenerative epitope was associated with impaired degradation and accumulation of degenerated protein in the temporal lobe of women with dementia.”

    The study concluded that mitochondria dysfunction in AD-related disorders may be a product of early alterations in the WM proteome by vascular dysfunction, hence as recently suggested, “the vascular component of disease is likely to exert a major influence on the clinical course of human dementias.”

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

    In summary, 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 toward future clinical interventions targeted at reducing dementia risk in both men and women.