Abstract
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.