Evaluation of In Vivo Efficacy of a Novel Microbial Therapy to Treat Cognitive Deficits in Alzheimers disease

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a leading cause of dementia, yet no effective therapeutic intervention is available for those in prodromal and early stages of AD. Restoration of functional and cognitive resilience in early disease stages is especially beneficial in many aspects as it could substantially extend the period of quality of life and delay the clinical onset of AD. In search of therapeutic targets for early disease stages, recent studies uncover a significant loss of TH+ neurons in locus coeruleus (LC) in patients with MCI and very early stages of AD. These neurons project to the hippocampus, where monoamine neurotransmitters, such as dopamine (DA) and norepinephrine (NE), modulate synaptic plasticity and neuronal functions relevant to memory and cognition. Thus, restoration of DA and NE levels in the hippocampus could retain cognitive resilience during early stages of AD. L-DOPA is a brain penetrating precursor drug for DA to treat Parkinson’s disease. Its therapeutic potency on AD has not been well investigated in humans in part due to lack of understanding in the pathological involvement of DA and NE in AD and development of neurobehavioral side-effects for frequent and long-term use. We, therefore, propose to comprehensively evaluate the therapeutic efficacy of L-DOPA by a novel method of administration in the mouse model recapitulating early stage of AD phenotypes. Unlike the traditional oral administration of L-DOPA multiple times a day, which results in fluctuation of L-DOPA in plasma and induces toxicity, we will give engineered commensal bacteria that produce L-DOPA (EcNrhaL-DOPA) in a sustained and non- pulsatile manner. Single administration of EcNrhaL-DOPA transiently resides in the gut for a couple of days and supply L-DOPA without disrupting the gut microbiota. This approach could effectively mitigate fluctuation- mediated side-effects and L-DOPA toxicity and maximize its therapeutic effects to restore brain DA and NE levels. As a first step towards evaluating its therapeutic benefits in the relevant AD mouse model, we propose to optimize the treatment regimen and dosage of EcNrhaL-DOPA administration in APP-KI and wildtype mice and to evaluate pharmacokinetics and any adverse toxicological effects in this application. The overall impact and translational significance of this proposed study are extremely high as this approach could not only work complementally with currently available drugs to treat AD but also significantly slow the progression of AD phenotypes from early stages to prevent conversion to full spectrum of AD. This novel technology is covered under USPTO Application # 20190262298, titled “L-DOPA microbiome therapy”.PROJECT NARRATIVE There is no effective treatment to alleviate neurobehavioral and memory decline for patients with MCI or early stage of Alzheimer’s disease (AD). Recent studies highlight a substantial loss of monoamine neurotransmitter inputs into the hippocampus during the early disease course and their contributions to cognitive functions, suggesting that restoration of monoamine neurotransmitters has significant therapeutic values to treat such symptoms. In this application, we will optimize the dosing regimen of our novel biogenic drug delivery system using commensal gut bacteria to give L-DOPA in a non-pulsatile manner in a mouse model of AD and assess pharmacokinetics and toxicity, in order to evaluate this as one of potential treatment strategy for AD.