Bioengineered microbiotic levodopa therapy improves cognition and reduces pathology in a rat model of Alzheimer's disease

Background and Purpose Degeneration of the pontine noradrenergic and midbrain dopaminergic systems contributes to cognitive‐behavioural disturbances during the prodromal stages of Alzheimer's disease (AD). We developed a genetically engineered, programmable probiotic Escherichia coli Nissle 1917 strain (EcN rha L‐DOPA ) capable of producing L‐3,4‐dihydroxyphenylalanine (L‐DOPA) in a sustained and titratable manner, thus offering a novel gut‐brain delivery mechanism to increase brain levels of noradrenaline and dopamine during the early stages of AD. Experimental Approach We replicated locus coeruleus (LC) projection system degeneration in AD by administering dopamine‐ β ‐hydroxylase IgG‐saporin immunotoxin into the prefrontal cortex of 6‐months‐old Tg344‐19 AD rats. The animals then received EcN rha L‐DOPA /benserazide or placebo by daily gavage for 6 weeks. We assessed cognitive‐behavioural function prior to postmortem assessments of amyloid‐β plaque load, glial cell activation and neuronal and synaptic markers. Gut colonization, along with plasma and brain L‐DOPA, dopamine, noradrenaline and metabolite levels, were also measured. Key Results EcN rha L‐DOPA displayed stable gut colonization and resulted in sustained therapeutic levels of L‐DOPA in plasma and brain, resulting in increased cortical and hippocampal noradrenaline levels. EcN rha L‐DOPA reduced anxiety‐like behaviour improved spatial and working memory. The treatment reduced forebrain A β plaque and MHC‐II antigen‐presenting microglial load. Additionally, EcN rha L‐DOPA increased protein levels of the dendritic spine marker PSD95. Conclusions and Implications This translational study suggests that EcN rha L‐DOPA modifies AD by boosting brain catecholamine production, reducing A β accumulation and neuroinflammation, promoting synaptic health, and enhancing cognitive function. Collectively, these results highlight EcN rha L‐DOPA as a promising preclinical engineered gut microbiome‐based therapeutic strategy for early‐stage AD.