From Bench to Bedside

Dr. Brinton’s investigation of the early events creating vulnerability for Alzheimer’s disease in the female brain led to 3 fundamental discoveries.

1. First, the aging transition of the menopause is in fact a energetic and neurological transition for the brain that leads to decline in glucose metabolism in brain. As glucose is the primary fuel to generate energy, ATP, in the brain even modest declines in glucose metabolism can lead to decline in synaptic and cognitive function.
2. Second, estrogen regulates the entire bioenergetic system of the brain, from glucose uptake into the brain to glucose metabolism and to mitochondrial ATP production.
3. Third, the loss of estrogenic control of glucose derived ATP leads to brain utilization of an alternative fuel, ketone bodies. Use of ketone bodies by the brain is reminiscent of starvation of the brain and of type 2 diabetes.  While this adaptation is advantageous in the short run, it can be disastrous in the long run.

Brinton formulated the bold hypothesis that the brain, to sustain function, would eventually use its own lipids found in white matter as fuel, thereby giving rise to one of the devastating hallmarks of Alzheimer’s disease, white matter degeneration. Brinton and her team have just submitted the outcomes of this research delineating the mechanistic pathway that leads to the brain catabolizing its own white matter for fuel. This finding, in combination with her discoveries, led to the development of a safe and effective alternative to estrogen therapy for the brain, PhytoSERMs, recently tested in an early phase clinical trial with encouraging results.  

In the early 1990s, Brinton made another remarkable discovery. Allopregnanolone (Allo), an endogenous neurosteroid, which promotes neural stem cell regeneration. This discovery came at time when there was little known about the regenerative potential of the brain. Brinton and her team have determined the mechanism of Allo action, while discovering that Allo could also reduce the burden of Alzheimer’s pathology in preclinical models of the disease.

Again, the strong foundation of rigorous mechanistic discovery science led to the translation and ultimate development of Allopregnanolone as the first regenerative therapeutic for Alzheimer’s and is currently being tested in an early phase clinical trial in persons with the disease.