An alpha (α)-secretase modulator for ameliorating Alzheimer’s Disease pathophysiology and cognitive impairment with neuroprotection

Alzheimer’s Disease

The symptoms of Alzheimer’s Disease (AD) are associated with progressive brain tissue shrinkage and death. In the early stages of AD, degeneration of cells in the hippocampus leads to short-term memory loss and reduced ability to perform routine tasks (cognitive disorders). As AD spreads through the cerebral cortex, judgment declines, emotional outbursts often occur and language skills become impaired.

AD progression leads to the death of additional nerve cells and loss of synapses and gradually worsening behavior changes, such as wandering and agitation. In the final stages, patients lose the ability to recognize faces, communicate and control bladder and bowel movements. The average time from diagnosis to death is 4 to 8 years, although it may take 20 years or more for the disease to run its course.

While there is some understanding of this disorder, there is still a lack of preventive and therapeutic remedies. AD is the third major cause of death in America and among the highest in the industrial world. AD is a widespread and significant neurological disorder that affects more than 4.5 million Americans and more than 10 million people worldwide. Epidemiologically, AD is anticipated to increase with the demographics of the aging populations in the United States, Europe, and Japan. Experts estimate that 22 million people around the world and more than 8 million Americans will be afflicted with AD by 2025.

Current Alzheimer’s Disease Drugs

Five prescription drugs are currently approved by the US Food and Drug Administration (FDA) to treat people who have been diagnosed with Alzheimer’s. While these drugs may treat the symptoms of AD, none of these medications is a cure for the disease.

Four of these medications, including Aricept®, are called cholinesterase inhibitors and are prescribed for the treatment of mild to moderate AD. They may help delay or prevent symptoms from becoming worse for a limited time and may help control some behavioral symptoms. The fifth approved medication, known as Namenda®, is believed to work by regulating glutamate, another important brain chemical that, when produced in excessive amounts, can cause excitotoxicity that leads to brain cell death. All of the drugs on the market today have serious side effects.

Current Approaches Being Evaluated for Treating Alzheimer’s Disease Drugs

Current research in AD prophylaxis and therapy is centered on identification of methods to decrease Beta-amyloid (Aβ) and the assembly of tau tangles, biochemical ‘signatures’ of AD which are the basis of cognitive decline. Beta (β)-secretase inhibitors have been extensively investigated, but have been difficult to translate into effective clinical treatments for AD. A recent Phase II AD clinical trial with the β-secretase inhibitor, LY2886721, was even halted because of liver toxicity. Gamma (γ)-secretase inhibitors may conceivably also reduce Aβ accumulation. However, a recent Phase III clinical trial with the γ-secretase inhibitor, ‘Semagacestat’ (LY-450139), was also halted because of evidence for accelerated AD dementia. Most of the recent clinical AD trial failures have been with β- and γ-secretase inhibitors.

Alpha (α)-Secretase Approach for Treating AD

Alpha (α)-secretase is another enzyme in the neuronal pathway that positively influences amyloid precursor protein, (‘APP’) processing. Both β-secretase and γ-secretase cleave APP to form insoluble amyloid plaques (Aβ) that set in motion tau fiber assembly. In contrast, α-secretase cleaves APP into the harmless and more soluble product, ‘sAPP-α’, that actually supports new synapse formation and is more readily cleared from the brain. Thus, unlike current strategies which aim to suppress Aβ plaque formation by minimizing β- and γ-secretase activities, our strategy to activate α-secretase effectively eliminates the substrate for β- amyloid generation, and at the same time leads to positive amyloid precursor processing to both prevent and reduce Aβ plaques in AD.