Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Understanding how age and biological sex influence the development of Alzheimer’s disease

Almutairi, Jawza 2022. Understanding how age and biological sex influence the development of Alzheimer’s disease. PhD Thesis, Cardiff University.
Item availability restricted.

[thumbnail of 2022AlmutairJPhD.pdf]
Preview
PDF - Accepted Post-Print Version
Download (50MB) | Preview
[thumbnail of Cardiff University Electronic Publication Form] PDF (Cardiff University Electronic Publication Form) - Supplemental Material
Restricted to Repository staff only

Download (91kB)

Abstract

Alzheimer’s disease is a highly complex neurodegenerative disease and multifactorial. Age is the most significant risk factor for Alzheimer’s disease (AD), with cases doubling every five years after 65. Thus, one of the most challenging areas in AD research is understanding what happens to the brain when it ages. Such insights could aid in distinguishing individuals who are more susceptible to developing AD during ageing. Over the last 25 years, brain ageing studies have looked at thousands of human brains to investigate the neuronal basis of agerelated cognitive decline. However, most of these studies enrolled adults over 60 years of age. Therefore, those studies overlooked the most significant period of neuroendocrine changes in a woman’s life, the menopause transition period. In the menopause phase, females undergo a significant decline in ovarian sex steroid production, including approximately 90% of oestrogen (E2) production. It is well documented that E2 has a neuroprotection function in the brain. Thus, the dramatic loss of sex steroids during menopause impacts multiple biological systems in the body, including the brain. In addition, despite documented sex disparities in the risk for dementia, the effect of biological sex and sex hormones on human brain ageing and AD development is understudied. Thus, in this thesis, it was hypothesized that an interrelationship between age and biological sex could impact brain structure and function during ageing and increase the susceptibility of women to develop AD. In this thesis, AD biomarkers and their processing proteins, along with E2-associated proteins expression, were investigated in frontal cortical brain samples from young (20-30), middle-aged (45-55), and elderly (70-90) males and females with no history of dementia, and in AD samples (70-90). A sex disparity during brain ageing and AD in the expression of AD biomarkers was reported in the first two experimental chapters, with females exhibiting agerelated upregulation in the levels of APP and its amyloidogenic enzymes. Also, Ab overproduction was observed in both sexes with advancing age, but its levels were significantly higher in aged female samples compared to aged males. In addition, higher levels of tau and GSK3b were found in the aged female frontal cortex compared to the male frontal cortex. In AD samples, these sex disparities in AD biomarkers were also visible in higher Ab levels and tau hyperphosphorylation in female AD patients compared to AD male patients. When E2- associated proteins were investigated, oestrogen receptor (ERa and ERb), in male samples only ERb and its downstream signalling molecules (Akt and ERK2) were upregulated in the VIII male frontal cortex with ageing, reported in chapter 5, while middle-aged female samples have shown a decline in the level of ERb and an age-related decrease in ERa in chapter 6. In AD samples, ERb expression declined in males in chapter 5, and in females, both ERa and ERb were decreased in chapter 6. Thus, the decline of ER in middle-aged females and AD of both sexes samples could indicate a reduction in E2 neuroprotection function; E2 can regulate Ab production, and it is the most significant neuroprotection function against AD. The neuroprotection of E2 against AD was illustrated in chapter 7, where the treatment of nontransfected female AD neuronal human induced pluripotent stem (hIPS) cells with E2 showed an apparent significant decline in Ab levels. An inter-relationship between brain ageing and biological sex in AD development was apparent in this project. The findings of this project could partly explain the sex-based variation in AD development. ER decline in the female frontal cortex during ageing and tremendous overproduction of Ab might highlight the differences between the sexes in the age of onset of AD. Preclinical AD could be initiated earlier in females because of losing the neuroprotective function of E2 during the menopause transition phase. Also, the thesis findings could indicate how important it is to investigate both sexes separately and not neglect to report female findings in preclinical and clinical studies where male samples were predominant.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Pharmacy
Subjects: Q Science > Q Science (General)
Date of First Compliant Deposit: 19 July 2022
Last Modified: 19 Jul 2022 11:11
URI: https://orca.cardiff.ac.uk/id/eprint/151366

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics