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Research Findings

Allopregnanolone (Allo), a natural hormone associated with pregnancy, promotes neurogenesis. It is now being studied in early Alzheimer disease.

Roberta Brinton PhD & Lon Schneider MD have been funded by the National Institutes on Aging to conduct a Phase I trial of allopregnanolone for mild Alzheimer disease.

Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of innate regeneration in brain. In a mouse model of Alzheimer’s disease, Allo induced generation of neurons and oligodendroglial cells. It also promoted white matter generation and cholesterol homeostasis. Finally, it reduced β-amyloid and neuroinflammatory burden.

Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and
their differentiation into neurons. In parallel, Allo activates systems to sustain cholesterol homeostasis and reduce β-amyloid generation.

To advance Allo into studies for chronic human neurological conditions, we examined translational and clinical parameters: dose, regimen, route, formulation, outcome measures, and safety regulations. A treatment regimen of once per week was optimal for regeneration and reduction in Alzheimer’s pathology. This regimen had a high safety profile following chronic exposure in aged normal and Alzheimer’s mice. Formulation of Allo has been developed for both preclinical and clinical testing in human beings.

1. Irwin RW, Brinton RD. Allopregnanolone as regenerative therapeutic for Alzheimer’s disease: translational development and clinical promise. Progress in neurobiology. Feb 2014;113:40-55.
2. Irwin RW, Solinsky CM, Brinton RD. Frontiers in therapeutic development of allopregnanolone for Alzheimer’s disease and other neurological disorders. Frontiers in cellular neuroscience. 2014;8:203.

Physical exercise decreases inflammation (e.g., TNF alpha) and preserves brain volume.

Braskie et al (2014) examined how prior physical activity intensity and TNFalpha related to MRI brain volumes in the Cardiovascular Health Study. Stability of measures was established for exercise intensity over 9 years and TNFalpha over 3 years in a subset of subjects who had these measurements at multiple time points. More intense physical activity intensity and lower serum TNFalpha were both associated with greater total brain volume on follow-up MRI scans.

Low TNFalpha, but not physical activity, was associated with greater volume of the inferior parietal lobule, a region previously associated with inflammation in AD patients. Physical activity and TNFalpha may independently influence brain structure in older adults.

Braskie MN, Boyle CP, Rajagopalan P, et al. Physical activity, inflammation, and volume of the aging brain. Neuroscience. Jul 25 2014;273:199-209.