Researchers have unlocked new insights into the molecular mechanism of Alzheimer’s disease (AD), which may explain why women are at a greater risk of developing AD than men. The study, published in Science Advances, describes a molecular link between nitric oxide signalling, oestrogen and the complement cascade in the pathogenesis of AD.
Too many unknowns in Alzheimer’s disease
AD is a neurological disorder that is characterised by progressive cognitive decline in old age. According to Alzheimer’s Research UK, women account for 61% of AD cases, for reasons that are not fully understood. The fatal disease has no approved treatment. This is largely because the underlying pathophysiology of AD is not fully discovered. The many unknowns in AD have hampered the development of effective therapies.
The complement cascade is a part of the innate immune system. Once activated, complement proteins ‘tag’ microbes and damaged cells for clearance by other immune cells. Complement proteins, such as C3, also promote inflammation. It is well-established that AD brains have higher levels of complement proteins than healthy brains. Recent research has demonstrated that synapse-damaging mechanisms in the brain are fuelled by the build-up of complement proteins like C3. This explains the cognitive decline seen in AD, because the connections between neurons are destroyed.
S-nitrosylation is a post-translational modification. A nitric oxide (NO)-related molecule binds to a sulphur (S) atom on a protein. This forms a SNO protein. Researchers suspect that S-nitrosylated C3 proteins (SNO-C3) contribute to the development of AD.
Researchers at the Scripps Research Institute (SRI) and the Massachusetts Institute of Technology (MIT) have investigated the mechanism of synaptic damage in AD. They analysed SNO proteins in AD brains and discovered that SNO-C3 was higher in the brains of female AD patients than male AD patients.
Stuart Lipton, senior author and Professor at the SRI said, “Our new findings suggest that chemical modification of a component of the complement system helps drive Alzheimer’s, and may explain, at least in part, why the disease predominantly affects women.”
Navigating SNO-storms in Alzheimer’s disease
The researchers conducted post-mortem autopsies on 40 human brains. There were 20 AD brains and 20 non-AD brains, and each group had an equal number of males and females. They conducted proteomic analysis to identify SNO proteins in AD brains.
They found that the levels of SNO-C3 in the brains of women with AD were 6 times higher than in the brains of men with AD. SNO-C3 levels were 34.2 times higher in female AD brains than female non-AD brains.
The researchers also showed that β-oestradiol (a steroidal oestrogen hormone) protected against the formation of SNO-C3. The researchers cultured human brain cells from stem cells. They increased NO production in the cells using inflammatory stimuli. The researchers then added β-oestradiol (a steroidal oestrogen hormone), which inhibited SNO-C3 production. The researchers showed that β-oestradiol likely protects premenopausal women against the formation of SNO-C3. Therefore, when oestrogen levels drop during menopause, the protective mechanism is weakened. This will increase S-nitrosylation of C3 and in turn, trigger microglia-driven synapse destruction.
Don’t let it SNO
The study highlights the damaging impact of SNO modifications and how this modification interlinks with β-oestradiol to drive AD in women. Future studies will be focussed on using de-nitrosylation compounds to reduce SNO-C3 in animal models. This will hopefully lead to studies in humans and finally an effective AD therapy.
Professor Lipton said, “Why women are more likely to get Alzheimer’s has long been a mystery, but I think our results represent an important piece of the puzzle that mechanistically explains the increased vulnerability of women as they age.”