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A possible mechanism for Alzheimer's dementia, which is more common in women



Women are 1.7 times more likely to be affected by Alzheimer's disease than men. Therefore, in addition to age and the gene encoding a particular form (ε4) of an apolipoprotein (APOE), female gender is a risk factor. As discussed in my blog post of 08/04/22, differences in sex hormones are thought to be responsible for this. However, variations in educational level and number of pregnancies may also play a role.


Although female menopause is associated with an increased risk of neurological disease, hormone replacement therapy has shown unclear or negative effects on dementia prevention. A recent study by Yan and colleagues now highlights a different molecular mechanism that makes increased susceptibility of the female brain to dementia-associated protein deposition likely. The protein in question is tau.


As described in my book on neurodegeneration in chapter 2.3.4, the amount of tau fibrils correlates with memory impairment. These intracellular tangles of phosphorylated and aggregated tau protein can be detected using markers (tracers) in positron emission tomography, but also in the cerebrospinal fluid (CSF). A large amount of phosphates bound to the protein, known as hyper-phosphorylation, prevents the normal degradation of tau and interferes with its binding to microtubules, the essential building blocks of the neuronal cytoskeleton. Both have a negative effect on cellular metabolism because tau is an important stabilizer of microtubules, which are also necessary for the directional transport of vesicles.


In the present work from the group of David Kang, who conducts his research at Case Western Reserve University in Cleveland (USA), it was shown that there is a greater tau burden in the female brain due to the physiologically higher expression of an enzyme called ubiquitin-specific peptidase (USP11). Increased tau deposition has been observed in PET imaging studies and neuropathologically in the brains of deceased women. In addition, higher levels of pTau are found in the CSF of women with mild cognitive impairment and in carriers of the aforementioned APOE ε4 allele.


Tau aggregation and degradation are controlled by post-translational modifications, including phosphorylation, acetylation, and ubiquitination. The latter controls the degradation of tau via the ubiquitin-proteasome or autophagy-lysosome pathway. The human genome encodes about 100 deubiquitinating enzymes (DUBs), about half of which are ubiquitin-specific peptidases (USPs). To investigate their role in regulating tau, Yan et al. screened so-called small interfering RNAs (siRNA) against 22 DUBs, all of which are expressed in the central nervous system. This allowed them to identify two positive regulators of tau: USP13 and USP11. Since USP11 is located on chromosome X and plays an important role in female biology, they hypothesized that this enzyme might contribute to female-specific susceptibility to AD.


In their paper, they present a series of data from cell cultures and human tissues that support this hypothesis: On the one hand, elevated USP11 levels in women compared to men lead to increased deubiquitination of tau at the amino acid lysine (K) 281, a change that drives pathological tau deposition by inhibiting degradation and promoting acetylation, making cognitive impairment more likely in women than men. On the other hand, USP11 accumulates in the brains of Alzheimer's patients regardless of gender. Here, the enzyme is frequently colocalized with tangles and neuropil fibrils.


However, the positive association of USP11 with tau pathology is much more pronounced in women than in men, consistent with elevated levels in women even at a preclinical stage of AD. Interestingly, estrogen overall increases the amount of USP11 in the brain. Males appear more likely to compensate for reduced levels of this enzyme by upregulating related USPs. Therefore, USP11 may provide a new pharmacological target for treatment of AD, particularly in females.


Reference:


Yan Y, Wang X, Chaput D, Shin M-K, Koh Y, Gan L, Pieper AA, Woo J-AA, Kang DE (2022) X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women. Cell 185:3913


Image credit: iStock/Cecilie-Arcurs.

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