Targeting early tau pathology: probiotic diet enhances cognitive function and reduces inflammation in a preclinical Alzheimer’s model

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Targeting early tau pathology: probiotic diet enhances cognitive function and reduces inflammation in a preclinical Alzheimer’s model

• Cassandra M. Flynn,
• Tamunotonye Omoluabi,
• Alyssa M. Janes,
• Emma J. Rodgers,
• Sarah E. Torraville,
• Brenda L. Negandhi,
• Timothy E. Nobel,
• Shyamchand Mayengbam &
• Qi Yuan 

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• 1 Mention

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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 (t₃ = -4.834) and S356 (t₃ = -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.