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We developed a genetically engineered, programmable probiotic\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:italic>Escherichia coli<\/jats:italic>\n                      <\/jats:styled-content>\n                      Nissle 1917 strain (EcN\n                      <jats:sup>rha<\/jats:sup>\n                      <jats:sub>L\u2010DOPA<\/jats:sub>\n                      ) capable of producing L\u20103,4\u2010dihydroxyphenylalanine (L\u2010DOPA) in a sustained and titratable manner, thus offering a novel gut\u2010brain delivery mechanism to increase brain levels of noradrenaline and dopamine during the early stages of AD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      We replicated locus coeruleus (LC) projection system degeneration in AD by administering dopamine\u2010\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2010hydroxylase IgG\u2010saporin immunotoxin into the prefrontal cortex of 6\u2010months\u2010old Tg344\u201019 AD rats. The animals then received EcN\n                      <jats:sup>rha<\/jats:sup>\n                      <jats:sub>L\u2010DOPA<\/jats:sub>\n                      \/benserazide or placebo by daily gavage for 6\u2009weeks. We assessed cognitive\u2010behavioural function prior to postmortem assessments of amyloid\u2010\u03b2 plaque load, glial cell activation and neuronal and synaptic markers. Gut colonization, along with plasma and brain L\u2010DOPA, dopamine, noradrenaline and metabolite levels, were also measured.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      EcN\n                      <jats:sup>rha<\/jats:sup>\n                      <jats:sub>L\u2010DOPA<\/jats:sub>\n                      displayed stable gut colonization and resulted in sustained therapeutic levels of L\u2010DOPA in plasma and brain, resulting in increased cortical and hippocampal noradrenaline levels. EcN\n                      <jats:sup>rha<\/jats:sup>\n                      <jats:sub>L\u2010DOPA<\/jats:sub>\n                      reduced anxiety\u2010like behaviour improved spatial and working memory. The treatment reduced forebrain A\n                      <jats:italic>\u03b2<\/jats:italic>\n                      plaque and MHC\u2010II antigen\u2010presenting microglial load. Additionally, EcN\n                      <jats:sup>rha<\/jats:sup>\n                      <jats:sub>L\u2010DOPA<\/jats:sub>\n                      increased protein levels of the dendritic spine marker PSD95.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>\n                      This translational study suggests that EcN\n                      <jats:sup>rha<\/jats:sup>\n                      <jats:sub>L\u2010DOPA<\/jats:sub>\n                      modifies AD by boosting brain catecholamine production, reducing A\n                      <jats:italic>\u03b2<\/jats:italic>\n                      accumulation and neuroinflammation, promoting synaptic health, and enhancing cognitive function. Collectively, these results highlight EcN\n                      <jats:sup>rha<\/jats:sup>\n                      <jats:sub>L\u2010DOPA<\/jats:sub>\n                      as a promising preclinical engineered gut microbiome\u2010based therapeutic strategy for early\u2010stage AD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70670","type":"journal-article","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T03:58:33Z","timestamp":1789790313000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bioengineered microbiotic levodopa therapy improves cognition and reduces pathology in a rat model of Alzheimer's disease"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5444-856X","authenticated-orcid":false,"given":"Mona","family":"Abdelhamid","sequence":"first","affiliation":[{"name":"Department of Translational Neuroscience, College of Human Medicine 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