Mohamed Hassan Farah - US grants

DESCRIPTION (provided by applicant): One of the hallmarks of Alzheimer's Disease (AD) pathology is the presence of neuritic plaques in the brains of affected individuals. These plaques are made up of extracellular deposits of amyloid beta peptide (Abeta) surrounded by dystrophic neurites, reactive astrocytes, and microglia. The Abeta peptide is derived from the human amyloid precursor protein (APP) by the activities of two secretases, beta-site APP cleaving enzyme 1 (BACE1) and gamma (a complex of proteins), which sequentially cleave the precursor. This proposal is built upon the intriguing observation that deletion of BACE1, the principal beta secretase in neurons, completely prevents Abeta deposition in a mouse model of Abeta amyloidosis. A critical question, however, remains: Is Abeta-mediated pathology reversible by inhibiting the activity of BACE1? This proposal tests the hypothesis that inhibiting BACE1 expression will ameliorate the development and evolution of Abeta-mediated pathology in this mouse model. The proposed studies are designed to test this hypothesis by two different experimental approaches: RNA interference (RNAi) to silence BACE1 (AIM 1); and inducible knock out of BACE1 (AIM 2). The studies will provide an important validation of BACE1 as a therapeutic target for AD.

DESCRIPTION (provided by applicant): Peripheral nerve damage and diseases are common health problems that often result in long-term functional deficits. Peripheral axons can regenerate and reinnervate target tissue following nerve injury or disease in young rodent animals. However, human axonal regeneration is very slow and both denervated Schwann cells, which provide a permissive micro-environment for regeneration, and target tissues are at risk for undergoing atrophy and death, precluding functional recover. This situation underscores the critical need for agents that can speed up axonal regeneration to restore function. A prime candidate for enhancing axonal regeneration is inhibition of Beta -Amyloid Cleaving Enzyme (BACE1). Recently, we show that genetic deletion and pharmacological inhibition of BACE1 markedly accelerate axonal regeneration in the injured peripheral nerves of mice. However, it is unclear how inhibition of BACE1 improves nerve regeneration. We postulate that accelerated nerve regeneration is due to blockade of BACE1 cleavage of two different BACE1 substrates. The two proposed substrates are the amyloid precursor protein (APP) in axons and tumor necrosis factor receptor 1 (TNFR1) on macrophages, which infiltrate injured nerves and clear the inhibitory myelin debris. We will systematically explore genetic manipulations of these two substrates in regard to accelerated axonal regeneration and rapid myelin debris removal seen in BACE1 KO mice. Equally importantly, we propose critical evaluations of a new and very attractive therapeutic approach (e.g. pharmacological inhibition of BACE1) to accelerate nerve regeneration in preclinical rodent models. As experimental models, we will employ peripheral nerve injury and chemotherapy-induced peripheral neuropathy in mice. To evaluate BACE1 inhibitors as a therapy for nerve damage and chemotherapy-induced peripheral neuropathy, we plan to take combined approaches of morphological, electrophysiological and behavioral studies. The proposed studies are highly relevant because faster rate of outgrowth associated with BACE1 inhibition could be useful in speeding nerve regeneration in human conditions. PUBLIC HEALTH RELEVANCE: Peripheral neuropathies and nerve injuries are major unmet health problems. Drugs originally developed for Alzheimer's disease, e.g. BACE1 inhibitors, could be a therapy for diseases of the peripheral nerve. These drugs can easily be applied as a therapy for nerve damage and diseases if the proposed studies in preclinical animal models show beneficial effects.

Peripheral nerve damage and disease are common health problems that often result in long-term functional deficits. Peripheral axons can regenerate and reinnervate target tissue following nerve injury or disease in young rodent animals. However, human axonal regeneration is very slow, putting both denervated Schwann cells, which provide a permissive microenvironment for regeneration, and target tissues at risk for undergoing atrophy and death, precluding functional recovery. This situation underscores the critical need for agents that can speed up axonal regeneration to restore function. Previously, we have shown that a genetic deletion of BACE1 markedly accelerates axonal regeneration in the injured peripheral nerves of mice. Our studies over the last funding period have focused on deciphering the cellular basis and molecular correlates of this enhanced nerve regeneration in BACE1 KO mice. We have also initiated investigations on the effectiveness of BACE1 inhibitors as potential therapies for nerve disorders. We revealed that BACE1 influences nerve regeneration through infiltrating macrophages and neuron-intrinsic mechanisms. BACE1 inhibitors reproduced the enhanced regeneration phenotype observed in BACE1 KO injured nerves. In this proposal, we plan to expand our research to investigate a causative link between candidate molecules and accelerated nerve regeneration in BACE1 KO mice. Of equal importance, we propose to evaluate whether a clinically applicable pharmacological BACE1 inhibitor accelerates functional and behavioral recovery following a nerve crush injury in mice. To accomplish these goals, we will: 1) use mice with BACE1 conditionally knocked out in macrophages crossed to TNF KO or TNFR1 KO mice (to bypass the perinatal death of the complete double KOs) to investigate whether there is a causative link between increased TNFR1 signaling and augmented macrophage influx; 2) test the hypothesis that a lack of processing of the cell adhesion molecules L1 and CHL1 in BACE1 KO neurons constitutes the neuronal component of accelerated axonal regeneration observed in vivo in BACE1 KO nerves; and 3) determine the efficacy and potency of an experimental Merck BACE1 inhibitor in accelerating functional recovery following a nerve injury using CatWalk, an automated gait analysis system, to evaluate behavioral recovery using a series of tests designed to analyze walking patterns. The results of these studies should provide general insight into the molecular mechanisms of accelerated nerve regeneration in BACE1 KO mice and would test BACE1 inhibitors as a new therapy for nerve trauma and disorders. This is attractive, given that the pharmaceutical industry is actively developing BACE1 inhibitors as candidate therapies for Alzheimer?s disease and is therefore amassing safety, efficacy, and biodistribution data on these molecules. The proposed studies are highly relevant because a faster rate of outgrowth associated with BACE1 inhibition could be useful in enhancing nerve regeneration in human conditions.