Improving Cognitive Function in AD Therapy Using a Combinatorial Approach of Reducing Disease Progression and Increasing Memory

Aβ is the main component of amyloid plaques found in the brains of Alzheimer patients. Production of Aβ is nearly stopped by inhibiting BACE1 enzyme. Therefore, BACE1 inhibitors are used to reduce Aβ production and amyloid deposition. But their use can lead to many side effects that impact learning and storage of memory. Therefore, it is critical to develop new therapeutic strategies. We propose to use BACE1 inhibitor drugs in combination with mGluR activator drugs. This combination therapy will stop the disease progression and help in memory retention at the same time. We will test our strategy in mice in the current study. Positive results from this study will provide Alzheimer patients a better quality of life.

Abnormal circulation of Abeta peptides in brain likely causes Alzheimer’s disease. Inhibition of BACE1, the enzyme that initiates Abeta production, is therefore being explored to treat AD patients. However clinically tested BACE1 inhibitors have failed to improve cognitive function despite strong reduction in Abeta generation. We observe BACE1 activity is essential for synaptic functions and ultimately cognitive abilities. Therefore, we explore molecular targets which can reverse synaptic impairments. One such candidate is mGluR PAM. We are developing treatment therapies combining BACE1 inhibitors for reducing amyloid deposition and mGluR PAM for countering synaptic deficits as a more effective approach for treating AD patients.