Mohamed Farah PhD
Associate Professor of Neurology
Associate Professor of Neurology
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 recovery. 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). We published a paper showing 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 candidate 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. In the coming years, 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 are evaluating 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 employ peripheral nerve injury in mice, and toxin-induced peripheral neuropathy in rodent models. We use combined approaches of morphological, electrophysiological and behavioral studies. These studies are highly relevant because faster rate of outgrowth associated with BACE1 inhibition could be useful in speeding nerve regeneration in human conditions.
Distal axonal degeneration is a hallmark of motor neuron diseases, and precedes clinical symptoms onset and motor neuron death both in animal models and human patients. Surviving intact motor axons extend axonal sprouts as a compensatory mechanism to denervated muscle areas, suggesting that an early intervention approach might be to enhance axonal sprouting. Recently, we characterized degeneration and regeneration of a pure long motor nerve. This is the lateral thoracic nerve (LTN) that innervates the back muscle, the cutaneus maximus muscle (CMM). The LTN/CMM system is an ideal system to investigate axonal sprouting and means to encourage axonal sprouting in motor neuron disease models. The LTN is comprised of fast-fatigable ??motor fibers and contains some of the shortest (to the high thoracic region) and the longest (to the region at the base of the tail) motor fibers in the rodent body. It innervates the CMM, which contains type II muscle fibers. The FF/type II motor axon/muscle classes are amongst the most vulnerable in the widely used mouse model of amyotrophic lateral sclerosis (ALS), the G93A SOD1 mouse. We plan to test whether genetic reduction and pharmacological inhibition of BACE1 can enhance axonal sprouting in the LTN and reinnervation of the CMM in G93A SOD1 mice at early stages of axoterminal degeneration.