A Novel Probiotic Formula, BIOCG, Protects Against Alzheimer’s-Related Cognitive Deficits via Regulation of Dendritic Spine Dynamics

Miao       Sun; Wenchenyang       Bao; Chengyu       Huang; Ziyue       Xia; Changliang       Zhang; Guangxian       Wang; Runxin       Wang; Jiangyu       Li; Shaun       Roux; Qian       Li; Dongmei       Zou; Kai       Ma; Xiaofeng       Bao

doi:10.2174/1567205018666211022091110

Abstract

Background: The brain-gut-microbiome axis has emerged as an important pathway through which perturbations in the gut and/or microbial microenvironment can impact neurological function. Such alterations have been implicated in a variety of neuropsychiatric disorders, including depression, anxiety, and Alzheimer’s Disease (AD) and the use of probiotics as therapy for these diseases remains promising. However, the mechanisms underlying the gut microenvironment’s influence on disease pathogenesis and therapy remain unclear.

Objective: The objective of this study is to investigate the effect of a novel probiotic formula, BIOCG, on cognitive function and pathobiological mechanisms, including amyloid processing and dendritic spine dynamics, in a mouse model of AD.

Methods: BIOCG was administered for 3 months to 3xTg or 3xTg; Thy1-YFP AD mice and functional outcomes were assessed via behavioral testing and electrophysiology. Mechanisms relevant to AD pathogenesis including dendritic spine morphology and turnover, Amyloid Precursor Protein (APP) processing and microglial phenotype were also evaluated. Finally, we sequenced fecal samples following probiotic treatment to assess the impact on gut microbial composition and correlate the changes with the above described measures.

Results: Mice treated with BIOCG demonstrated preserved cognitive abilities and stronger Long- Term Potentiation (LTP), spontaneous Excitatory Postsynaptic Currents (sEPSC), and glutamate-induced LTPs, indicative of functional and electrophysiological effects. Moreover, we observed attenuated AD pathogenesis, including reduced Amyloid Beta (Aβ) burden, as well as more mature dendritic spines in the BIOCG-treated. Our finding of changes in microglial number and phenotype in the treatment group suggests that this formulation may mediate its effects via attenuation of neuroinflammation. Sequencing data confirmed that the gut microbiome in treated mice was more varied and harbored a greater proportion of “beneficial” bacteria.

Conclusion: Overall, our results indicate that treatment with BIOCG enhances microbial diversity and, through gut-brain axis interactions, attenuates neuroinflammation to produce histologic and functional improvement in AD pathogenesis.

Keywords: Alzheimer's Disease (AD), probiotics, in vivo imaging, dendritic spine, synaptic plasticity, inflammation.

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[1] 
World Alzheimer Report 2019. 2019. Available from: https://www.alzint.org/resource/world-alzheimer-report-2019/
[2] 
Reddy PH, Oliver DMA. Amyloid beta and phosphorylated tau-induced defective autophagy and mitophagy in Alzheimer’s risease. Cells  2019; 8(5): E488.
[http://dx.doi.org/10.3390/cells8050488] [PMID: 31121890] 
[3] 
Mungenast AE, Siegert S, Tsai LH. Modeling Alzheimer’s disease with human induced pluripotent stem (iPS) cells. Mol Cell Neurosci  2016; 73: 13-31.
[http://dx.doi.org/10.1016/j.mcn.2015.11.010] [PMID: 26657644] 
[4] 
Dorsey ER, George BP, Leff B, Willis AW. The coming crisis: obtaining care for the growing burden of neurodegenerative conditions. Neurology  2013; 80(21): 1989-96.
[http://dx.doi.org/10.1212/WNL.0b013e318293e2ce] [PMID: 23616157] 
[5] 
Chen Y, Fu AKY, Ip NY. Synaptic dysfunction in Alzheimer’s disease: Mechanisms and therapeutic strategies. Pharmacol Ther  2019; 195: 186-98.
[http://dx.doi.org/10.1016/j.pharmthera.2018.11.006] [PMID: 30439458] 
[6] 
Kokubo H, Kayed R, Glabe CG, Yamaguchi H. Soluble Abeta oligomers ultrastructurally localize to cell processes and might be related to synaptic dysfunction in Alzheimer’s disease brain. Brain Res  2005; 1031(2): 222-8.
[http://dx.doi.org/10.1016/j.brainres.2004.10.041] [PMID: 15649447] 
[7] 
Bomba M, Ciavardelli D, Silvestri E, et al. Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals. Cell Death Dis  2013; 4: e612.
[http://dx.doi.org/10.1038/cddis.2013.139] [PMID: 23640454] 
[8] 
Lecca D, Bader M, Tweedie D, et al. (-)-Phenserine and the prevention of pre-programmed cell death and neuroinflammation in mild traumatic brain injury and Alzheimer’s disease challenged mice. Neurobiol Dis  2019; 130: 104528.
[http://dx.doi.org/10.1016/j.nbd.2019.104528] [PMID: 31295555] 
[9] 
Mueller SG, Schuff N, Yaffe K, Madison C, Miller B, Weiner MW. Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer’s disease. Hum Brain Mapp  2010; 31(9): 1339-47.
[http://dx.doi.org/10.1002/hbm.20934] [PMID: 20839293] 
[10] 
Cho C, MacDonald R, Shang J, Cho MJ, Chalifour LE, Paudel HK. Early growth response-1-mediated down-regulation of drebrin correlates with loss of dendritic spines. J Neurochem  2017; 142(1): 56-73.
[http://dx.doi.org/10.1111/jnc.14031] [PMID: 28369888] 
[11] 
Hooper PL, Durham HD, Török Z, Hooper PL, Crul T, Vígh L. The central role of heat shock factor 1 in synaptic fidelity and memory consolidation. Cell Stress Chaperones  2016; 21(5): 745-53.
[http://dx.doi.org/10.1007/s12192-016-0709-1] [PMID: 27283588] 
[12] 
Huo R, Zeng B, Zeng L, et al. Microbiota modulate anxiety-like behavior and endocrine abnormalities in hypothalamic-pituitary-adrenal axis. Front Cell Infect Microbiol  2017; 7: 489.
[http://dx.doi.org/10.3389/fcimb.2017.00489] [PMID: 29250490] 
[13] 
Diaz Heijtz R, Wang S, Anuar F, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA  2011; 108(7): 3047-52.
[http://dx.doi.org/10.1073/pnas.1010529108] [PMID: 21282636] 
[14] 
Bercik P. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology  2011; 141(2): 599-609.
[http://dx.doi.org/10.1053/j.gastro.2011.04.052] 
[15] 
Vogt NM, Kerby RL, Dill-McFarland KA, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep  2017; 7(1): 13537.
[http://dx.doi.org/10.1038/s41598-017-13601-y] [PMID: 29051531] 
[16] 
Akbari E, Asemi Z, Daneshvar Kakhaki R, et al. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: A randomized, double-blind and controlled trial. Front Aging Neurosci  2016; 8: 256.
[http://dx.doi.org/10.3389/fnagi.2016.00256] [PMID: 27891089] 
[17] 
Minter MR, Hinterleitner R, Meisel M, et al. Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1ΔE9 murine model of Alzheimer’s disease. Sci Rep  2017; 7(1): 10411.
[http://dx.doi.org/10.1038/s41598-017-11047-w] [PMID: 28874832] 
[18] 
Mo M, Eyo UB, Xie M, et al. Microglial P2Y12 receptor regulates seizure-induced neurogenesis and immature neuronal projections. J Neurosci  2019; 39(47): 9453-64.
[http://dx.doi.org/10.1523/JNEUROSCI.0487-19.2019] [PMID: 31597724] 
[19] 
Eyo UB, Peng J, Swiatkowski P, Mukherjee A, Bispo A, Wu LJ. Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus. J Neurosci  2014; 34(32): 10528-40.
[http://dx.doi.org/10.1523/JNEUROSCI.0416-14.2014] [PMID: 25100587] 
[20] 
Yoshihara Y, De Roo M, Muller D. Dendritic spine formation and stabilization. Curr Opin Neurobiol  2009; 19(2): 146-53.
[http://dx.doi.org/10.1016/j.conb.2009.05.013] [PMID: 19523814] 
[21] 
Pchitskaya E, Bezprozvanny I. Dendritic spines shape analysis-classification or clusterization? Perspective. Front Synaptic Neurosci  2020; 12: 31.
[http://dx.doi.org/10.3389/fnsyn.2020.00031] [PMID: 33117142] 
[22] 
Kwon HB, Sabatini BL. Glutamate induces de novo growth of functional spines in developing cortex. Nature  2011; 474(7349): 100-4.
[http://dx.doi.org/10.1038/nature09986] [PMID: 21552280] 
[23] 
Wu Q, Sun M, Bernard LP, Zhang H. Postsynaptic density 95 (PSD-95) serine 561 phosphorylation regulates a conformational switch and bidirectional dendritic spine structural plasticity. J Biol Chem  2017; 292(39): 16150-60.
[http://dx.doi.org/10.1074/jbc.M117.782490] [PMID: 28790172] 
[24] 
DiBona VL, Zhu W, Shah MK, et al. Loss of Par1b/MARK2 primes microglia during brain development and enhances their sensitivity to injury. J Neuroinflammation  2019; 16(1): 11.
[http://dx.doi.org/10.1186/s12974-018-1390-3] [PMID: 30654821] 
[25] 
Kauppinen TM, Swanson RA. Poly(ADP-ribose) polymerase-1 promotes microglial activation, proliferation, and matrix metalloproteinase-9-mediated neuron death. J Immunol  2005; 174(4): 2288-96.
[http://dx.doi.org/10.4049/jimmunol.174.4.2288] [PMID: 15699164] 
[26] 
Kauppinen TM, Suh SW, Higashi Y, et al. Poly(ADP-ribose)polymerase-1 modulates microglial responses to amyloid β. J Neuroinflammation  2011; 8(1): 152.
[http://dx.doi.org/10.1186/1742-2094-8-152] [PMID: 22051244] 
[27] 
Wang XF, Liu JJ, Xia J, Liu J, Mirabella V, Pang ZP. Endogenous glucagon-like peptide-1 suppresses high-fat food intake by reducing synaptic drive onto mesolimbic dopamine neurons. Cell Rep  2015; 12(5): 726-33.
[http://dx.doi.org/10.1016/j.celrep.2015.06.062] [PMID: 26212334] 
[28] 
Maqueshudul Haque Bhuiyan M, Mohibbullah M, Hannan MA, et al. Undaria pinnatifida promotes spinogenesis and synaptogenesis and potentiates functional presynaptic plasticity in hippocampal neurons. Am J Chin Med  2015; 43(3): 529-42.
[http://dx.doi.org/10.1142/S0192415X15500330] [PMID: 25967666] 
[29] 
Jamet S, Bubnell J, Pfister P, Tomoiaga D, Rogers ME, Feinstein P. In vitro mutational analysis of the β2 adrenergic receptor, an in vivo surrogate odorant receptor. PLoS One  2015; 10(10): e0141696.
[http://dx.doi.org/10.1371/journal.pone.0141696] [PMID: 26513247] 
[30] 
Chunchai T, Thunapong W, Yasom S, et al. Decreased microglial activation through gut-brain axis by prebiotics, probiotics, or synbiotics effectively restored cognitive function in obese-insulin resistant rats. J Neuroinflammation  2018; 15(1): 11.
[http://dx.doi.org/10.1186/s12974-018-1055-2] [PMID: 29316965] 
[31] 
Sun M, Asghar SZ, Zhang H. The polarity protein Par3 regulates APP trafficking and processing through the endocytic adaptor protein Numb. Neurobiol Dis  2016; 93: 1-11.
[http://dx.doi.org/10.1016/j.nbd.2016.03.022] [PMID: 27072891] 
[32] 
Kaur H, Nagamoto-Combs K, Golovko S, Golovko MY, Klug MG, Combs CK. Probiotics ameliorate intestinal pathophysiology in a mouse model of Alzheimer’s disease. Neurobiol Aging  2020; 92: 114-34.
[http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.009] [PMID: 32417748] 
[33] 
Xiao J, Katsumata N, Bernier F, et al. Probiotic bifidobacterium breve in improving cognitive functions of older adults with suspected mild cognitive impairment: A randomized, double-blind, placebo-controlled trial. J Alzheimer's Dis  2020; 77(1): 137-47.
[http://dx.doi.org/10.3233/JAD-200488] [PMID: 32623402] 
[34] 
Kobayashi Y, Sugahara H, Shimada K, et al. Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer’s disease. Sci Rep  2017; 7(1): 13510.
[http://dx.doi.org/10.1038/s41598-017-13368-2] [PMID: 29044140] 
[35] 
Guilherme MDS, Nguyen VTT, Reinhardt C, Endres K. Impact of gut microbiome manipulation in 5xFAD mice on alzheimer’s disease-like pathology. Microorganisms  2021; 9(4): 815.
[http://dx.doi.org/10.3390/microorganisms9040815] [PMID: 33924322] 
[36] 
Andreyeva A, Nieweg K, Horstmann K, et al. C-terminal fragment of N-cadherin accelerates synapse destabilization by amyloid-β. Brain  2012; 135(Pt 7): 2140-54.
[http://dx.doi.org/10.1093/brain/aws120] [PMID: 22637581] 
[37] 
Ramalho RM, Nunes AF, Dias RB, et al. Tauroursodeoxycholic acid suppresses amyloid β-induced synaptic toxicity in vitro and in APP/PS1 mice. Neurobiol Aging  2013; 34(2): 551-61.
[http://dx.doi.org/10.1016/j.neurobiolaging.2012.04.018] [PMID: 22621777] 
[38] 
Nomura I, Takechi H, Kato N. Intraneuronally injected amyloid β inhibits long-term potentiation in rat hippocampal slices. J Neurophysiol  2012; 107(9): 2526-31.
[http://dx.doi.org/10.1152/jn.00589.2011] [PMID: 22338026] 
[39] 
Firbank MJ, Blamire AM, Teodorczuk A, Teper E, Mitra D, O’Brien JT. Diffusion tensor imaging in Alzheimer’s disease and dementia with Lewy bodies. Psychiatry Res  2011; 194(2): 176-83.
[http://dx.doi.org/10.1016/j.pscychresns.2011.08.002] [PMID: 21955457] 
[40] 
Mattia D, Babiloni F, Romigi A, et al. Quantitative EEG and dynamic susceptibility contrast MRI in Alzheimer’s disease: a correlative study. Clin Neurophysiol  2003; 114(7): 1210-6.
[http://dx.doi.org/10.1016/S1388-2457(03)00085-3] [PMID: 12842717] 
[41] 
Rezaei Asl Z, Sepehri G, Salami M. Probiotic treatment improves the impaired spatial cognitive performance and restores synaptic plasticity in an animal model of Alzheimer’s disease. Behav Brain Res  2019; 376: 112183.
[http://dx.doi.org/10.1016/j.bbr.2019.112183] [PMID: 31472194] 
[42] 
Sun N, Ni X, Wang H, et al. Probiotic Lactobacillus johnsonii BS15 prevents memory dysfunction induced by chronic high-fluorine intake through modulating intestinal environment and improving gut development. Probiotics Antimicrob Proteins  2020; 12(4): 1420-38.
[http://dx.doi.org/10.1007/s12602-020-09644-9] [PMID: 32166711] 
[43] 
Varnum MM, Ikezu T. The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Arch Immunol Ther Exp (Warsz)  2012; 60(4): 251-66.
[http://dx.doi.org/10.1007/s00005-012-0181-2] [PMID: 22710659] 
[44] 
Streit WJ, Xue QS. Human CNS immune senescence and neurodegeneration. Curr Opin Immunol  2014; 29: 93-6.
[http://dx.doi.org/10.1016/j.coi.2014.05.005] [PMID: 24908174] 
[45] 
Jin SC, Benitez BA, Karch CM, et al. Coding variants in TREM2 increase risk for Alzheimer’s disease. Hum Mol Genet  2014; 23(21): 5838-46.
[http://dx.doi.org/10.1093/hmg/ddu277] [PMID: 24899047] 
[46] 
Condic M, Oberstein TJ, Herrmann M, et al. N-truncation and pyroglutaminylation enhances the opsonizing capacity of Aβ-peptides and facilitates phagocytosis by macrophages and microglia. Brain Behav Immun  2014; 41: 116-25.
[http://dx.doi.org/10.1016/j.bbi.2014.05.003] [PMID: 24876064] 
[47] 
Isidro RA, Lopez A, Cruz ML, et al. The probiotic VSL#3 modulates colonic macrophages, inflammation, and microflora in acute trinitrobenzene sulfonic acid colitis. J Histochem Cytochem  2017; 65(8): 445-61.
[http://dx.doi.org/10.1369/0022155417718542] [PMID: 28692320] 
[48] 
Liu YW, Liu WH, Wu CC, et al. Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naïve adult mice. Brain Res  2016; 1631: 1-12.
[http://dx.doi.org/10.1016/j.brainres.2015.11.018] [PMID: 26620542] 
[49] 
Guo C, Yang ZH, Zhang S, et al. Intranasal lactoferrin enhances α-secretase-dependent amyloid precursor protein processing via the ERK1/2-CREB and HIF-1α pathways in an Alzheimer’s disease mouse model. Neuropsychopharmacology  2017; 42(13): 2504-15.
[http://dx.doi.org/10.1038/npp.2017.8] [PMID: 28079060] 
[50] 
Ries M, Loiola R, Shah UN, Gentleman SM, Solito E, Sastre M. The anti-inflammatory Annexin A1 induces the clearance and degradation of the amyloid-β peptide. J Neuroinflammation  2016; 13(1): 234.
[http://dx.doi.org/10.1186/s12974-016-0692-6] [PMID: 27590054] 
[51] 
Peng Y, Sun J, Hon S, et al. L-3-n-butylphthalide improves cognitive impairment and reduces amyloid-beta in a transgenic model of Alzheimer’s disease. J Neurosci  2010; 30(24): 8180-9.
[http://dx.doi.org/10.1523/JNEUROSCI.0340-10.2010] [PMID: 20554868] 
[52] 
Sun M, Huang C, Wang H, Zhang H. Par3 regulates polarized convergence between APP and BACE1 in hippocampal neurons. Neurobiol Aging  2019; 77: 87-93.
[http://dx.doi.org/10.1016/j.neurobiolaging.2019.01.023] [PMID: 30784815] 
[53] 
Sun M, Zhang H. Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1. Neurobiol Aging  2017; 60: 129-40.
[http://dx.doi.org/10.1016/j.neurobiolaging.2017.08.024] [PMID: 28946017] 
[54] 
Wei MY, Shi S, Liang C, et al. The microbiota and microbiome in pancreatic cancer: more influential than expected. Mol Cancer  2019; 18(1): 97.
[http://dx.doi.org/10.1186/s12943-019-1008-0] [PMID: 31109338] 
[55] 
Huang SY, Chen LH, Wang MF, et al. Lactobacillus paracasei PS23 delays progression of age-related cognitive decline in senescence accelerated mouse prone 8 (SAMP8) mice. Nutrients  2018; 10(7): E894.
[http://dx.doi.org/10.3390/nu10070894] [PMID: 30002347] 
[56] 
Andisi VF, Hinojosa CA, de Jong A, Kuipers OP, Orihuela CJ, Bijlsma JJ. Pneumococcal gene complex involved in resistance to extracellular oxidative stress. Infect Immun  2012; 80(3): 1037-49.
[http://dx.doi.org/10.1128/IAI.05563-11] [PMID: 22215735] 
[57] 
Salehipour Z, Haghmorad D, Sankian M, et al. Bifidobacterium animalis in combination with human origin of Lactobacillus plantarum ameliorate neuroinflammation in experimental model of multiple sclerosis by altering CD4+ T cell subset balance. Biomed Pharmacother  2017; 95: 1535-48.
[http://dx.doi.org/10.1016/j.biopha.2017.08.117] [PMID: 28946394] 
[58] 
O’Hagan C, Li JV, Marchesi JR, Plummer S, Garaiova I, Good MA. Long-term multi-species Lactobacillus and Bifidobacterium dietary supplement enhances memory and changes regional brain metabolites in middle-aged rats. Neurobiol Learn Mem  2017; 144: 36-47.
[http://dx.doi.org/10.1016/j.nlm.2017.05.015] [PMID: 28602659] 
[59] 
Cheng R, Xu T, Zhang Y, et al. Lactobacillus rhamnosus GG and Bifidobacterium bifidum TMC3115 can affect development of hippocampal neurons cultured in vitro in a strain-dependent manner. Probiotics Antimicrob Proteins  2020; 12(2): 589-99.
[http://dx.doi.org/10.1007/s12602-019-09571-4] [PMID: 31286435] 
[60] 
Mohammadi G, Dargahi L, Naserpour T, et al. Probiotic mixture of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 attenuates hippocampal apoptosis induced by lipopolysaccharide in rats. Int Microbiol  2019; 22(3): 317-23.
[http://dx.doi.org/10.1007/s12602-019-09571-4] [PMID: 30810993] 
[61] 
Tamtaji OR, Heidari-Soureshjani R, Mirhosseini N, et al. Probiotic and selenium co-supplementation, and the effects on clinical, metabolic and genetic status in Alzheimer’s disease: a randomized, double-blind, controlled trial. Clin Nutr  2019; 38(6): 2569-75.
[http://dx.doi.org/10.1016/j.clnu.2018.11.034] [PMID: 30642737] 
[62] 
Athari Nik Azm S, Djazayeri A, Safa M, et al. Probiotics improve insulin resistance status in an experimental model of Alzheimer’s disease. Med J Islam Repub Iran  2017; 31: 103.
[http://dx.doi.org/10.14196/mjiri.31.103] [PMID: 29951404] 
[63] 
van Beek AA, Sovran B, Hugenholtz F, et al. Supplementation with Lactobacillus plantarum WCFS1 prevents decline of mucus barrier in colon of accelerated aging Ercc1-/Δ7 Mice. Front Immunol  2016; 7: 408.
[http://dx.doi.org/10.3389/fimmu.2016.00408] [PMID: 27774093] 

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DOI https://dx.doi.org/10.2174/1567205018666211022091110	Print ISSN 1567-2050
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Current Alzheimer Research

A Novel Probiotic Formula, BIOCG, Protects Against Alzheimer’s-Related Cognitive Deficits via Regulation of Dendritic Spine Dynamics

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Current Alzheimer Research

A Novel Probiotic Formula, BIOCG, Protects Against Alzheimer’s-Related Cognitive Deficits via Regulation of Dendritic Spine Dynamics

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