After serial behavioral tests, fecal short-chain fatty acid levels and AD-related pathology were assessed in these mice. Results Our findings show that intracerebroventricular injection of streptozotocin accelerated cognitive dysfunction associated with increasing levels of glycogen synthase kinase 3 beta (GSK3) activity, tau protein phosphorylation at the T231 site (pT231), amyloid- (A) deposition, amyloid- protein precursor (APP), -site APP-cleaving enzyme (BACE1), gliosis, fecal propionic acid (PPA) levels and cognition-related neuronal loss and decreasing postsynaptic density protein 95 (PSD95) levels in 3??Tg-AD mice. PR65A for synaptophysin protein. 12906_2021_3426_MOESM1_ESM.docx (2.7M) GUID:?1690F596-3319-4D3C-A923-19F0EAAE62D9 Data Availability StatementThe dataset used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Abstract Background According to recent evidence, psychobiotics exert beneficial effects on central nervous system-related diseases, such as mental disorders. PS128 (PS128), a novel psychobiotic strain, improves motor function, depression, and anxiety behaviors. However, the psychobiotic effects and mechanisms of PS128 in Alzheimers disease (AD) remain to be explored. Objectives The goal of the current study was to evaluate the beneficial effects of PS128 and to further elucidate its mechanism in AD mice. Methods PS128 (1010 colony-forming unit (CFU)/ml) was administered via oral gavage (o.g.) to 6-month-old male wild-type B6 and 3??Tg-AD mice (harboring the PS1M146V, APPswe and TauP30IL transgenes) that received an intracerebroventricular injection of streptozotocin (icv-STZ, 3?mg/kg) or vehicle (saline) for 33?days. After serial behavioral tests, fecal short-chain fatty acid levels BI-1347 and AD-related pathology were assessed in these mice. Results Our findings show that intracerebroventricular injection of streptozotocin accelerated cognitive dysfunction associated with increasing levels of glycogen synthase kinase 3 beta (GSK3) activity, tau protein phosphorylation BI-1347 at the T231 site (pT231), amyloid- (A) deposition, amyloid- protein precursor (APP), -site APP-cleaving enzyme (BACE1), gliosis, fecal propionic acid (PPA) levels and cognition-related neuronal loss and decreasing postsynaptic density protein 95 (PSD95) levels in 3??Tg-AD mice. PS128 supplementation effectively prevented the damage induced by intracerebroventricular injection of streptozotocin in 3??Tg-AD mice. Conclusions Based on the experimental results, intracerebroventricular injection of streptozotocin accelerates the progression of AD in the 3??Tg-AD mice, primarily by increasing the levels of gliosis, which were mediated by the propionic acid and glycogen synthase kinase 3 beta pathways. PS128 supplementation prevents damage induced by intracerebroventricular injection of streptozotocin by regulating the propionic acid levels, BI-1347 glycogen synthase kinase 3 beta activity, and gliosis in 3??Tg-AD mice. Therefore, we suggest that PS128 supplementation is a potential strategy to prevent and/or delay the progression of AD. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-021-03426-8. MTCC1325 and (C29) were also shown to attenuate memory impairment in D-galactose-induced AD animal models [14, 15]. The reports described above suggest that probiotic supplementation may be an effective method to delay AD progression. PS128 (PS128) is a psychobiotic isolated from fu-tsai, a traditional Taiwanese fermented vegetable food product that has been reported to reduce anxiety and depression by decreasing inflammation and cortisol levels [16, 17]. Recent evidence also suggests that PS128 psychobiotics attenuate hyperactive behaviors by modulating the microbiota-gut-brain axis [18]. However, the relationship between SCFAs derived from microbial metabolites and PS128 psychobiotics in individuals with AD remains unclear. An intricate relationship exists between the gut microbiota and the development of types 1, 2 and 3 diabetes [19]. Type 3 diabetes has been proposed as a common term for AD [20]. The impairment of brain glucose uptake/metabolism is a common early abnormality in individuals with AD [21]. Accumulating evidence also reveals an important role for brain glucose hypometabolism in the process of cognitive decline and aging [22C25]. An intracerebroventricular injection of the diabetogenic toxin streptozotocin (icv-STZ) exacerbates memory disturbances and AD-like neurochemical changes in the brains of 3??Tg-AD mice (harboring the PS1M146V, APPswe and TauP30IL transgenes) by impairing insulin signaling [26, 27]. Therefore, icv-STZ was used to accelerate AD progression in 6-month-old male 3??Tg-AD mice (the age before typical AD pathologies develop) in the present study. We aim to examine the beneficial effects of PS128 on 3??Tg-AD mice treated with icv-STZ and to elucidate the role of SCFAs in 3??Tg-AD mice treated with PS128 and icv-STZ. Our results showed that the administration of icv-STZ accelerated the disease progression of AD, which might result from gliosis occurring through increased GSK3 activity and fecal PPA levels in 3??Tg-AD mice. PS128 supplementation effectively prevented the damage induced by icv-STZ by reducing the fecal PPA levels, GSK3 activity, and gliosis in 3??Tg-AD mice. Methods Animals C57BL/6?J male mice and 3??Tg-AD mice on a B6/129 hybrid genetic background were purchased from the National Breeding Center for Laboratory Animals and Jackson Laboratory (004807; Bar Harbor, ME, USA). 3??Tg-AD mice were backcrossed for more than 10 generations.