A stem cell secretome delays functional decline and supresses inflammation in two distinct models of neurodegeneration

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a rapidly increasing global prevalence. Current pharmacological interventions offer symptomatic relief but do not modify disease progression. Secretome-based therapeutics have emerged as a potential disease-modifying strategy, given their capacity to influence multiple pathological pathways, including amyloid burden, reactive gliosis, and neuronal survival. Early clinical studies support the safety and potential efficacy of these approaches, indicating mechanisms involving neuroprotection, neurodegeneration, and modulation of neuroinflammation, processes central to AD pathology. In the present study, we investigated the therapeutic efficacy of multipotent stromal cell (MSC)-derived secretomes produced by a specific platform (Secretomix) in two distinct mouse models of neurodegenerative disease: An AD model characterized by amyloid pathology, and a motor neurone disease (MND) model exhibiting TDP-43 protein aggregation. Administration of the MSC secretome resulted in a positive modulation of the behavioural phenotype in the AD model, and reduction in the rate of decline of motor co-ordination (attenuated the progression of motor deficits) in the MND model. In the latter, these functional benefits were accompanied by a measurable reduction in neuroinflammatory responses but without direct alteration of standard neuropathological markers. Additionally, ex vivo assays using human peripheral blood demonstrated broad anti-inflammatory activity of the MSC secretome, providing a potential mechanistic basis for the in vivo observations. Collectively, these findings support further investigation of MSC-derived secretomes as a promising therapeutic approach for neurodegenerative disorders, with relevance across proteinopathies characterised by distinct molecular pathways. Significance Statement Here we demonstrate the efficacy of a stem cell secretome in ameliorating cognitive and behavioural phenotypes in different models of neurodegeneration. These models represent distinct neuropathological features that are unaffected by stem cell secretome treatment but share common features of modulation of inflammation post stem cell secretome treatment. This study highlights the therapeutic potential of stem cell secretomes in the treatment of neurodegenerative conditions with an already existing neuropathology.