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ARTICLE | NEUROSCIENCE | Mutations of proteins precede disease progression.


Mutations occur for a variety of reasons, known or unknown, and create a number of proteins14


:


■ ParkinsonÕs disease. Protein affected: α-synuclein; protein mutated: A53T and A30P


■ AlzheimerÕs disease. Protein affected: α-Amyloid precursor; protein mutated: Protein AD1, AD2, AD3, AD4, Tau, presenilin 1 and 2, α-macroglobulin


■ HuntingtonÕs disease. Protein affected: huntingtin; protein mutated: HD


■ Spinocerebellar ataxia. Protein affected: ataxin; protein mutated: Sca.


Approximately 30% of cases of dementia of the AlzheimerÕs type can be attributed to genetic factors16


. A


positive family history coupled with the ApoE4 gene is the strongest risk factor for late-onset AD (LOAD). Middle-aged offspring of families with a parental history of LOAD often present with higher blood pressure, lower ankleÐb rachial indices (measure of peripheral atherosclerosis), and increased proinflammatory cytokines17


. The molecular mechanisms underlying the


pathogenesis of AD and other related neurodegenerative diseases are not well clarified, but increased oxidative stress and mitochondrial dysfunction14 misfolded proteins14 calcium homeostasis19


, neuroinflammation18


leading to neurodegeneration. Chaperones are ubiquitous, stress-induced proteins


that achieve a functionally-active 3D structure, preventing misfolded or aggregated structures, and inhibiting events that lead to aggregation. Chaperones reduce the severity of many neurodegenerative conditions, as well as other protein-misfolding diseases14


.


Gender differences in neurodegenerative diseases Men are more likely to present with PD as D2 receptor declination occurs early in this population cohort compared with women20


with AD. The Framingham Study21 . and increased with


, who are more likely to present estimated that the


prevalence of AlzheimerÕs type dementia was 30.5/1000 for men and 48.2/1000 for women22 advancing age23


Oestrogen can prevent vascular disease, as well as


improving blood-flow in diseased vessels, including blood-flow in regions of the brain affected by AD. Oestrogen also has direct effects on neuronal function that may play an important role in the preservation and repair of neurons. These effects of oestrogen on the central nervous system suggest that the hormone may be effective not only in the prevention of dementia, but also in the treatment and prevention of neurodegenerative disease. Oestrogens also protect against stroke and other environmental insults24


. Increasing evidence has revealed significant gender


differences in the pathophysiology and outcomes of acute neurological injury. Lesser susceptibility to post-ischaemic and post-traumatic brain injury in females has been observed in experimental models25


50 ❚ . June 2012 | prime-journal.com


The greater neuroprotection afforded to females is likely owing to the effects of circulating oestrogens and progestins. In fact, exogenous administration of the hormones has been shown to improve outcomes after cerebral ischaemia and traumatic brain injury in experimental models. The mechanisms by which oestrogen and progesterone provide such neuroprotection are complex, and probably depend on the type and severity of injury, as well as the type and concentration of hormone present. The putative effects of oestrogen include preservation


of autoregulatory function, an antioxidant effect, reduction of Aβ production and neurotoxicity, reduced excitotoxicity, increased expression of the antiapoptotic factor Bcl-2, and activation of mitogen-activated protein kinase pathways. It is hypothesised that a number of these neuroprotective mechanisms can be linked to oestrogenÕs ability to act as a potent chemical antioxidant. Progesterone, on the other hand, has a membrane stabilising effect that reduces the damage caused by lipid peroxidation and may also provide neuroprotection by suppressing neuronal hyperexcitability24


. Many other hormones are involved in wellbeing and


the prevention of neurodegenerative disease, such as erythropoyetin, vitamin D (a steroid hormone), progesterone, testosterone, DHEA, pregnenolone, leptin, insulin, melatonin, and selective oestrogen receptor modulators (SERMs). It is possible to counteract the ageing process by


, accumulation of , and perturbed


have been identified as factors


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