Researchers report the first clear, sex-specific differences in protein levels and structure in the white matter and mitochondria of brains from men and women with dementia, according to a study published in the open access journal Molecular Brain.
Previous epidemiological studies have shown that women face a higher risk of dementia than men, but the molecular reasons behind this disparity have been unclear. A research team from Nanyang Technological University, Singapore, used an unbiased proteomics approach to examine post-mortem brain tissue and discovered distinct differences in protein composition and modifications between female and male dementia patients. These findings improve our understanding of why dementia risk and severity may be greater in women and could inform future drug development strategies.
Associate Professor Sze Siu Kwan, a co-author of the study, emphasized the urgency of this work: “The number of dementia patients is projected to triple by 2050. Identifying the key molecular mechanisms driving dementia is critical. Our findings—and follow-up research—could directly inform knowledge about disease progression and help guide the development of therapeutic interventions.”
The investigators analyzed temporal lobe tissue from five male and five female dementia patients as well as ten healthy controls. They focused on two key compartments: the white matter, which contains axons and the myelin sheath that insulates them, and mitochondria, the organelles that produce cellular energy. Using quantitative proteomics allowed the researchers to survey thousands of proteins without pre-selecting targets, revealing changes in abundance and structural modifications associated with dementia.
One major discovery was a pattern of degenerative protein modifications (DPMs) concentrated on myelin basic protein (MBP). MBP is essential for forming and maintaining the myelin sheath that electrically insulates axons and enables reliable signal transmission across brain circuits. DPMs—chemical changes that degrade normal protein function, analogous to rust weakening metal—were far more pronounced on MBP in female patients than in males. These modifications included increased citrullination and deamidation, which the study linked to impaired degradation of damaged MBP and accumulation of non-functional MBP in white matter. Loss of effective myelination interferes with nerve impulse conduction and can disrupt communication between brain regions, contributing to cognitive decline.
In addition to white matter alterations, the study revealed mitochondrial protein disturbances consistent with mitochondrial dysfunction. Mitochondria generate the ATP needed for essential cellular processes, and their impairment can cause energy deficiency, oxidative stress, and ultimately cell injury or death. Female dementia patients in this study showed greater down-regulation of mitochondrial ATP subunits and cytochromes compared with male patients, suggesting more severe mitochondrial compromise in women.
Lead author Xavier Gallart-Palau commented on the methodological strengths of the project: “Proteomics provides an unbiased, discovery-driven way to identify molecular differences between male and female dementia patients that may not be apparent with conventional techniques.” By detecting post-translational modifications and changes in protein abundance across cellular compartments, proteomic profiling can point to pathways that contribute to sex-specific vulnerability.
Taken together, these molecular signatures in white matter and mitochondria offer new insight into why women may experience greater risk and more severe forms of dementia. The observed differences—particularly the accumulation of modified, non-functional MBP and the greater decline in mitochondrial proteins in women—highlight potential targets for therapeutic intervention. Targeting the mechanisms that underlie DPMs or supporting mitochondrial function could be promising strategies to reduce disease progression in both sexes, with special attention to female-specific pathways.
Source: Anne Korn – BioMed Central
Image Source: The image is in the public domain.
Original Research: Full open access research titled “Gender differences in white matter pathology and mitochondrial dysfunction in Alzheimer’s disease with cerebrovascular disease” by Xavier Gallart-Palau et al., published in Molecular Brain on 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
Epidemiological data show higher dementia risk in women, yet the molecular neuropathology behind this gender disparity is not well defined. This study applied unbiased, discovery-driven quantitative proteomics to investigate how sex influences the molecular profile of Alzheimer’s disease with cerebrovascular disease (AD + CVD) in the temporal lobe.
Results
Proteomic analysis revealed modulation of several redox-related proteins and identified sex-specific alterations in white matter and mitochondrial proteomes in female patients. Functional analysis highlighted increased citrullination of arginine and deamidation of glutamine residues in myelin basic protein (MBP) among women, which impaired clearance of degenerated MBP and led to accumulation of dysfunctional MBP in white matter. Female patients also exhibited down-regulation of ATP subunits and cytochromes, indicating more pronounced mitochondrial impairment.
Conclusions
The study demonstrates that gender-linked changes in white matter and mitochondrial proteomes contribute to temporal lobe neuropathology in AD + CVD and help explain sex differences in dementia risk and severity.
“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