Targeting early tau pathology: probiotic diet enhances cognitive function and reduces inflammation in a preclinical Alzheimer’s model
Abstract Background Alzheimer’s disease (AD) remains incurable, yet its long prodromal phase offers a crucial window for early intervention. Pretangle tau, a precursor to neurofibrillary tangles, plays a key role in early AD pathogenesis. Intervening in pretangle tau pathology could significantly de...
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2025-01-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-025-01674-1 |
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| author | Cassandra M. Flynn Tamunotonye Omoluabi Alyssa M. Janes Emma J. Rodgers Sarah E. Torraville Brenda L. Negandhi Timothy E. Nobel Shyamchand Mayengbam Qi Yuan |
| author_facet | Cassandra M. Flynn Tamunotonye Omoluabi Alyssa M. Janes Emma J. Rodgers Sarah E. Torraville Brenda L. Negandhi Timothy E. Nobel Shyamchand Mayengbam Qi Yuan |
| author_sort | Cassandra M. Flynn |
| collection | DOAJ |
| description | Abstract Background Alzheimer’s disease (AD) remains incurable, yet its long prodromal phase offers a crucial window for early intervention. Pretangle tau, a precursor to neurofibrillary tangles, plays a key role in early AD pathogenesis. Intervening in pretangle tau pathology could significantly delay the progression of AD. The gut-brain axis, increasingly recognized as a contributor to AD, represents a promising therapeutic target due to its role in regulating neuroinflammation and neurodegeneration. While probiotics have shown cognitive benefits in amyloid-centered AD models, their effect on pretangle tau pathology remains elusive. Methods This study evaluates the effects of probiotics in a rat model of preclinical AD, specifically targeting hyperphosphorylated pretangle tau in the locus coeruleus. TH-CRE rats (N = 47; 24 females and 23 males) received either AAV carrying pseudophosphorylated human tau (htauE14) or a control virus at 3 months of age. Probiotic or control diets were administered at 9–12 months, with blood and fecal samples collected for ELISA and 16S rRNA gene sequencing. Behavioral assessments were conducted at 13–14 months, followed by analysis of brain inflammation, blood-brain barrier integrity, and GSK-3β activation. Results Rats expressing pseudophosphorylated tau displayed impairment in spatial Y-maze (F 1,39 = 4.228, p = 0.046), spontaneous object location (F 1,39 = 6.240, p = 0.017), and olfactory discrimination (F 1,39 = 7.521, p = 0.009) tests. Phosphorylation of tau at S262 (t 3 = -4.834) and S356 (t 3 = -3.258) in the locus coeruleus was parallelled by GSK-3β activation in the hippocampus (F 1,24 = 10.530, p = 0.003). Probiotic supplementation increased gut microbiome diversity (F 1,31 = 8.065, p = 0.007) and improved bacterial composition (F 1,31 = 3.4867, p = 0.001). The enhancement in gut microbiomes was associated with enhanced spatial learning (p < 0.05), reduced inflammation indexed by Iba-1 (F 1,25 = 5.284, p = 0.030) and CD-68 (F 1,26 = 8.441, p = 0.007) expression, and inhibited GSK-3β in female rats (p < 0.01 compared to control females). Conclusions This study underscores the potential of probiotics to modulate the gut-brain axis and mitigate pretangle tau-related pathology in preclinical AD. Probiotic supplementation could offer a novel early intervention strategy for AD, highlighting the pivotal role of gut health in neurodegeneration. |
| format | Article |
| id | doaj-art-2ba3b688fd4345ef935020137e4bc5ea |
| institution | Kabale University |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-2ba3b688fd4345ef935020137e4bc5ea2025-01-19T12:12:57ZengBMCAlzheimer’s Research & Therapy1758-91932025-01-0117111510.1186/s13195-025-01674-1Targeting early tau pathology: probiotic diet enhances cognitive function and reduces inflammation in a preclinical Alzheimer’s modelCassandra M. Flynn0Tamunotonye Omoluabi1Alyssa M. Janes2Emma J. Rodgers3Sarah E. Torraville4Brenda L. Negandhi5Timothy E. Nobel6Shyamchand Mayengbam7Qi Yuan8Biomedical Sciences, Faculty of Medicine, Memorial University of NewfoundlandBiomedical Sciences, Faculty of Medicine, Memorial University of NewfoundlandBiomedical Sciences, Faculty of Medicine, Memorial University of NewfoundlandBiomedical Sciences, Faculty of Medicine, Memorial University of NewfoundlandBiomedical Sciences, Faculty of Medicine, Memorial University of NewfoundlandBiomedical Sciences, Faculty of Medicine, Memorial University of NewfoundlandBiomedical Sciences, Faculty of Medicine, Memorial University of NewfoundlandBiochemistry Department, Faculty of Science, Memorial University of NewfoundlandBiomedical Sciences, Faculty of Medicine, Memorial University of NewfoundlandAbstract Background Alzheimer’s disease (AD) remains incurable, yet its long prodromal phase offers a crucial window for early intervention. Pretangle tau, a precursor to neurofibrillary tangles, plays a key role in early AD pathogenesis. Intervening in pretangle tau pathology could significantly delay the progression of AD. The gut-brain axis, increasingly recognized as a contributor to AD, represents a promising therapeutic target due to its role in regulating neuroinflammation and neurodegeneration. While probiotics have shown cognitive benefits in amyloid-centered AD models, their effect on pretangle tau pathology remains elusive. Methods This study evaluates the effects of probiotics in a rat model of preclinical AD, specifically targeting hyperphosphorylated pretangle tau in the locus coeruleus. TH-CRE rats (N = 47; 24 females and 23 males) received either AAV carrying pseudophosphorylated human tau (htauE14) or a control virus at 3 months of age. Probiotic or control diets were administered at 9–12 months, with blood and fecal samples collected for ELISA and 16S rRNA gene sequencing. Behavioral assessments were conducted at 13–14 months, followed by analysis of brain inflammation, blood-brain barrier integrity, and GSK-3β activation. Results Rats expressing pseudophosphorylated tau displayed impairment in spatial Y-maze (F 1,39 = 4.228, p = 0.046), spontaneous object location (F 1,39 = 6.240, p = 0.017), and olfactory discrimination (F 1,39 = 7.521, p = 0.009) tests. Phosphorylation of tau at S262 (t 3 = -4.834) and S356 (t 3 = -3.258) in the locus coeruleus was parallelled by GSK-3β activation in the hippocampus (F 1,24 = 10.530, p = 0.003). Probiotic supplementation increased gut microbiome diversity (F 1,31 = 8.065, p = 0.007) and improved bacterial composition (F 1,31 = 3.4867, p = 0.001). The enhancement in gut microbiomes was associated with enhanced spatial learning (p < 0.05), reduced inflammation indexed by Iba-1 (F 1,25 = 5.284, p = 0.030) and CD-68 (F 1,26 = 8.441, p = 0.007) expression, and inhibited GSK-3β in female rats (p < 0.01 compared to control females). Conclusions This study underscores the potential of probiotics to modulate the gut-brain axis and mitigate pretangle tau-related pathology in preclinical AD. Probiotic supplementation could offer a novel early intervention strategy for AD, highlighting the pivotal role of gut health in neurodegeneration.https://doi.org/10.1186/s13195-025-01674-1Preclinical Alzheimer’s diseasePretangle tauGut-brain axisProbioticsNeuroinflammationBlood-brain barrier |
| spellingShingle | Cassandra M. Flynn Tamunotonye Omoluabi Alyssa M. Janes Emma J. Rodgers Sarah E. Torraville Brenda L. Negandhi Timothy E. Nobel Shyamchand Mayengbam Qi Yuan Targeting early tau pathology: probiotic diet enhances cognitive function and reduces inflammation in a preclinical Alzheimer’s model Alzheimer’s Research & Therapy Preclinical Alzheimer’s disease Pretangle tau Gut-brain axis Probiotics Neuroinflammation Blood-brain barrier |
| title | Targeting early tau pathology: probiotic diet enhances cognitive function and reduces inflammation in a preclinical Alzheimer’s model |
| title_full | Targeting early tau pathology: probiotic diet enhances cognitive function and reduces inflammation in a preclinical Alzheimer’s model |
| title_fullStr | Targeting early tau pathology: probiotic diet enhances cognitive function and reduces inflammation in a preclinical Alzheimer’s model |
| title_full_unstemmed | Targeting early tau pathology: probiotic diet enhances cognitive function and reduces inflammation in a preclinical Alzheimer’s model |
| title_short | Targeting early tau pathology: probiotic diet enhances cognitive function and reduces inflammation in a preclinical Alzheimer’s model |
| title_sort | targeting early tau pathology probiotic diet enhances cognitive function and reduces inflammation in a preclinical alzheimer s model |
| topic | Preclinical Alzheimer’s disease Pretangle tau Gut-brain axis Probiotics Neuroinflammation Blood-brain barrier |
| url | https://doi.org/10.1186/s13195-025-01674-1 |
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