M Paul Murphy’s research while affiliated with University of Kentucky and other places

Accumulation of amyloid-β (Aβ) plays an important role in Alzheimer’s disease (AD) pathology. There is growing evidence that disordered sleep may accelerate AD pathology by impeding the physiological clearance of Aβ from the brain that occurs in normal sleep. Therapeutic strategies for improving sleep quality may therefore help slow disease progression. It is well documented that the composition and dynamics of sleep are sensitive to ambient temperature. We therefore compared Aβ pathology and sleep metrics derived from polysomnography in 12-month-old female 3xTg-AD mice (n = 8) exposed to thermoneutral temperatures during the light period over four weeks to those of age- and sex-matched controls (n = 8) that remained at normal housing temperature (22⁰C) during the same period. The treated group experienced greater proportions of slow wave sleep (SWS)—i.e., epochs of elevated 0.5-2 Hz slow wave activity during non-rapid eye movement (NREM) sleep—compared to controls. Assays performed on mouse brain tissue harvested at the end of the experiment showed that exposure to thermoneutral temperatures significantly reduced levels of DEA-soluble (but not RIPA- or FA-soluble) Aβ40 and Aβ42 in the hippocampus, though not in the cortex. With both groups pooled together and without regard to treatment condition, NREM sleep continuity and any measure of SWS within NREM at the end of the treatment period were inversely correlated with DEA-soluble Aβ40 and Aβ42 levels, again in the hippocampus but not in the cortex. These findings suggest that experimental manipulation of SWS could offer useful clues into the mechanisms and treatment of AD.

Alzheimer’s disease (AD) affects more women than men, with women throughout the menopausal transition potentially being the most under researched and at-risk group. Sleep disruptions, which are an established risk factor for AD, increase in prevalence with normal aging and are exacerbated in women during menopause. Sex differences showing more disrupted sleep patterns and increased AD pathology in women and female animal models have been established in literature, with much emphasis placed on loss of circulating gonadal hormones with age. Interestingly, increases in gonadotropins such as follicle stimulating hormone are emerging to be a major contributor to AD pathogenesis and may also play a role in sleep disruption, perhaps in combination with other lesser studied hormones. Several sleep influencing regions of the brain appear to be affected early in AD progression and some may exhibit sexual dimorphisms that may contribute to increased sleep disruptions in women with age. Additionally, some of the most common sleep disorders, as well as multiple health conditions that impair sleep quality, are more prevalent and more severe in women. These conditions are often comorbid with AD and have bi-directional relationships that contribute synergistically to cognitive decline and neuropathology. The association during aging of increased sleep disruption and sleep disorders, dramatic hormonal changes during and after menopause, and increased AD pathology may be interacting and contributing factors that lead to the increased number of women living with AD.

Alzheimer’s disease (AD) affects more women than men, with women throughout the menopausal transition potentially being the most under researched and at-risk group. Sleep disruptions, which are an established risk factor for AD, increase in prevalence with normal aging and are exacerbated in women during menopause. Sex differences showing more disrupted sleep patterns and increased AD pathology in women and female animal models have been established in literature, with much emphasis placed on loss of circulating gonadal hormones with age. Interestingly, increases in gonadotropins such as follicle stimulating hormone are emerging to be a major contributor to AD pathogenesis and may also play a role in sleep disruption, perhaps in combination with other lesser studied hormones. Several sleep influencing regions of the brain appear to be affected early in AD progression and some may exhibit sexual dimorphisms that may contribute to increased sleep disruptions in women with age. Additionally, some of the most common sleep disorders, as well as multiple health conditions that impair sleep quality, are more prevalent and more severe in women. These conditions are often comorbid with AD and have bi-directional relationships that contribute synergistically to cognitive decline and neuropathology. The association during aging of increased sleep disruption and sleep disorders, dramatic hormonal changes during and after menopause, and increased AD pathology may be interacting and contributing factors that lead to the increased number of women living with AD.

There is a clear need of dietary recommendations or guidelines at both population and/or individual levels, to prevent the Alzheimer's disease or reduce its symptoms. Though data from cellular and animal models of Alzheimer's disease indicate that dietary lipids ameliorate cognitive deficits or neuropathology associated with this disease. However, the data from the present dietary studies are not standardized. Most dietary research in Alzheimer's disease has not examined and compared the differential effects of each fatty acid with other dietary nutrients. Nutrients, particularly different types of fatty acids, absorb, metabolize, and interact with other lipid or nutrients differently in animals and humans with compromised neurological status. Studies in animals and tissue culture should consider such limitations to predict a better response in patients with Alzheimer's disease. The present commentary emphasizes the significance of examining composite lipids/nutrients rather than single fatty acid or nutrient. This report also provides a brief overview of the key factors need to be considered while planning in-vitro, in-vivo or clinical experiments on the effects of dietary fatty acids on Alzheimer's disease. It is to hope that keeping these considerations in mind more judicious use of dietary regimens will speed up the progress of dietary research into the prevention of Alzheimer's disease.

There is a clear need of dietary recommendations or guidelines at both population and/or individual levels, to prevent the Alzheimer's disease or reduce its symptoms. Though data from animal and cellular models of Alzheimer's disease indicate that dietary lipids ameliorate cognitive deficits or neuropathology associated with this disease. However, the data from the present dietary studies are not standardized. Most dietary research in Alzheimer's disease has not examined and compared the differential effects of each fatty acid with other dietary nutrients. Nutrients, particularly different types of fatty acids, absorb, metabolize, and interact with other lipid or nutrients differently in animals and human with compromised neurological status. Studies in animals and tissue culture should consider such limitation to predict a better response in patients with Alzheimer's disease. The present commentary reinforces the importance of studying composite lipids/nutrients rather than single fatty acid or nutrients. This report also provides a brief overview of the key factors need to be considered while planning in-vitro, invivo or clinical experiments on the effects of dietary fatty acids on Alzheimer's disease. It is to hope that keeping these considerations in mind more judicious use of dietary regimens will accelerate the progress of research into the prevention of Alzheimer's disease.

Clinical studies suggest that traumatic brain injury (TBI) hastens cognitive decline and development of neuropathology resembling brain aging. Blood-brain barrier (BBB) disruption following TBI may contribute to the aging process by deregulating substance exchange between the brain and blood. We evaluated the effect of juvenile TBI (jTBI) on these processes by examining long-term alterations of BBB proteins, β-amyloid (Aβ) neuropathology, and cognitive changes. A controlled cortical impact was delivered to the parietal cortex of male rats at postnatal day 17, with behavioral studies and brain tissue evaluation at 60 days post-injury (dpi). Immunoglobulin G extravasation was unchanged, and jTBI animals had higher levels of tight-junction protein claudin 5 versus shams, suggesting the absence of BBB disruption. However, decreased P-glycoprotein (P-gp) on cortical blood vessels indicates modifications of BBB properties. In parallel, we observed higher levels of endogenous rodent Aβ in several brain regions of the jTBI group versus shams. In addition at 60 dpi, jTBI animals displayed systematic search strategies rather than relying on spatial memory during the water maze. Together, these alterations to the BBB phenotype after jTBI may contribute to the accumulation of toxic products, which in turn may induce cognitive differences and ultimately accelerate brain aging.Journal of Cerebral Blood Flow & Metabolism advance online publication, 14 November 2012; doi:10.1038/jcbfm.2012.154.

The accumulation of β-amyloid protein (Aβ) is a key risk factor in the development of Alzheimer's disease. The ovarian sex steroid hormones 17β-estradiol (E(2)) and progesterone (P(4)) have been shown to regulate Aβ accumulation, although the underlying mechanism(s) remain to be fully elucidated. In this study, we investigate the effects of E(2) and P(4) treatment on the expression levels of Aβ clearance factors including insulin-degrading enzyme, neprilysin, endothelin-converting enzyme 1 and 2, angiotensin-converting enzyme, and transthyretin, both in primary neuron cultures and female rat brains. Our results show that E(2) and P(4) affect the expression levels of several Aβ clearance factors in dose- and time-dependent manners. Most notably, expression of insulin-degrading enzyme is significantly increased by both hormones in cultured neurons and in vivo and is inversely associated with the soluble Aβ levels in vivo. These findings further define sex steroid hormone actions involved in regulation of Aβ, a relationship potentially important to therapeutic approaches aimed at reducing risk of Alzheimer's disease.