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

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-3 beta activation. Results: Rats expressing pseudophosphorylated tau displayed impairment in spatial Y-maze (F-1,F-39 = 4.228, p = 0.046), spontaneous object location (F-1,F-39 = 6.240, p = 0.017), and olfactory discrimination (F-1,F-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-3 beta activation in the hippocampus (F-1,F-24 = 10.530, p = 0.003). Probiotic supplementation increased gut microbiome diversity (F-1,F-31 = 8.065, p = 0.007) and improved bacterial composition (F-1,F-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,F-25 = 5.284, p = 0.030) and CD-68 (F-1,F-26 = 8.441, p = 0.007) expression, and inhibited GSK-3 beta 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.