- Targeting Hyperactive Circuits
- Dietary Supplements
- Microtubule-Stabilizing Drug and Tau Pathology
- Next-Generation Phosphodiesterase Inhibitors
The prevalence of Alzheimer’s disease is expected to rise as the population ages, increasing the urgency of developing new treatments. Drugs approved by the U.S. Food and Drug Administration to treat Alzheimer’s include cholinesterase inhibitors and memantine, both of which support neurotransmitters important to memory function. These drugs provide symptomatic relief and may slow symptoms of cognitive decline in some people for a limited time. However, they neither halt nor reverse disease progression because they do not target the underlying molecular pathways believed to be involved in Alzheimer’s.
Translational research is a multidisciplinary, multistep process that uses basic science discoveries to develop medicines or other interventions that improve health. The process of discovering and developing drugs for neurological disorders like Alzheimer’s is extremely challenging and expensive. One estimate found it takes 10 to 15 years from the discovery of a new therapeutic target until a new drug reaches the market, with an average cost of about $1.8 billion (Paul et al., 2010).
Intensive translational research is underway to identify and test therapies that interfere with various processes involved in the development of Alzheimer’s. Accumulation of toxic forms of amyloid and tau proteins are major hallmarks of Alzheimer’s disease, and much translational research has targeted those proteins. Increasingly, researchers are exploring other molecular and cellular pathways that may be involved in Alzheimer’s, based on our expanding knowledge of possible mechanisms, including glial cell activation, inflammation, and abnormal neuronal circuit activity.
Some neural circuits are underactive in Alzheimer’s disease, whereas others appear to be hyperactive, as neurons show abnormal firing activity. Circuit hyperactivity can cause epileptic seizures, and there is an increased incidence of epilepsy and seizure-like brain activity in people with Alzheimer’s. Researchers at the Gladstone Institute of Neurological Disease, San Francisco, studied the effects of different antiepileptic drugs in Alzheimer’s model mice (Sanchez et al, 2012). One of the seven drugs studied, levetiracetam, reduced abnormal neuronal electrical activity. Treating Alzheimer’s model mice with the drug for 4 weeks reversed many of their Alzheimer’s-like symptoms, including synaptic abnormalities in the hippocampus, behavioral abnormalities, and learning and memory deficits.
This study supports the idea that hyperactive neuronal circuits contribute to cognitive deficits in Alzheimer’s, and it suggests that drugs that calm neuronal hyperactivity should be explored as Alzheimer’s therapeutics.
During certain conditions, such as fasting and endurance exercise, the body breaks down fat as well as glucose for energy, and in the process produces small molecules called ketone bodies. Based on past research suggesting that ketones may protect neurons, a team at the National Institute on Aging Intramural Research Program, Baltimore, fed Alzheimer’s model mice a ketone-rich diet for 4 to 7 months (Kashiwaya et al., 2013). The ketone diet improved learning and memory ability and reduced anxiety in the Alzheimer’s mice. The improvements in brain function were accompanied by reduced levels of beta-amyloid and tau pathology in the hippocampus and other brain regions critical for learning and memory.
Vitamin D Supplements
Vitamin D deficiency has been associated with increased risk of age-related cognitive decline, and vitamin D supplements appear to protect brain health in animals. To examine the possible mechanisms involved, investigators at Wayne State University, Detroit, gave young and old rats vitamin D supplements or a placebo for 3 weeks and then tested their learning and memory (Briones and Darwish, 2012).
The older rats given the supplement showed reduced cognitive decline, as well as improved levels of biomarkers associated with brain inflammation and decreased brain beta-amyloid burden. In contrast, vitamin D had no effect on either inflammatory markers or cognitive function in young rats. While further research in humans in needed, these findings suggest that vitamin D supplements be further investigated as a way to stave off age-related cognitive decline.
Healthy neurons are supported internally by structures called microtubules, protein rods that help transport nutrients and molecules from the cell body to its axons, the cable-like structures that transmit messages in the brain. However, in Alzheimer’s and certain other neurodegenerative diseases, the protein tau—which normally binds to and stabilizes microtubules—undergoes changes that cause it to detach from the microtubule and eventually form tangles. These tangles cause the microtubules to start falling apart. As a result, the transport system collapses, and the neuron is damaged.
Drugs that stabilize microtubules have been developed as anticancer agents. University of Pennsylvania, Philadelphia, researchers studied the potential therapeutic effects of one of these drugs, epothilone D (EpoD), in mouse models that produce an abnormal form of tau and, over time, show damaged axons and cognitive impairment (Zhang et al., 2012).
After the mice began showing evidence of damaged neurons and cognitive deficits, the researchers treated them with EpoD for 3 months. Following the treatment, the condition of the axons and microtubules improved, as did cognitive performance. This study suggests that microtubule-stabilizing drugs developed to treat cancer might also prove helpful in Alzheimer’s and other neurodegenerative diseases involving tau pathology.
The drug sildenafil (Viagra®) was found to improve synaptic and cognitive function in mouse models of Alzheimer’s. Scientists know that sildenafil treats Alzheimer’s in mice by inhibiting the cellular enzyme phosphodiesterase type 5 (PDE5). However, using sildenafil and similar drugs to treat Alzheimer’s in humans raises concerns about potential side effects, including visual disturbances and back pain.
Researchers at Columbia University, New York City, wanted to harness the Alzheimer’s-related benefits of sildenafil and related drugs while avoiding their negative side effects. They designed a new set of compounds that inhibit PDE5 more powerfully and selectively than sildenafil (Fiorito et al., 2013). The researchers then administered one of these compounds, 7a, to Alzheimer’s model mice and found that it reversed memory deficits. In the hippocampus—a part of the brain vital to learning and memory—7a also reversed beta-amyloid impairment of synaptic function. This new class of PDE5 inhibitors may have potential as an Alzheimer’s therapeutic.