INTRODUCTION: The typical symptoms of Alzheimer's disease (AD) are cognitive impairment, disrupted spatial orientation, behavioral and psychiatric abnormalities, and later motor deficits. Neuropathologically, AD is characterized by deposits of pathological forms of endogenous proteins - amyloid-β, and neurofibrillary tau protein pathology. The latter closely correlates with brain atrophy and clinical impairment. Pharmacological therapies for these pathologies are largely absent, raising the question whether non-pharmacological interventions could be efficacious. Environmental factors can play a role in the manifestation of AD. It is unknown whether enriched environment (EE) can ameliorate the propagation of protein aggregates or their toxic components. METHODS: We injected insoluble tau extracts from human brains with AD (600 or 900 ng per animal) into hippocampi of SHR72 transgenic rats that express non-mutated truncated human tau 151-391/4R, but usually do not develop hippocampal tangles. The rats had either standard housing, or could access an EE 5×/week for 3 months. Behavioral analysis included the Morris Water Maze (MWM). Histological analysis was used to assess the propagation of tau pathology. RESULTS: Animals exposed to EE performed better in the MWM (spatial acquisition duration and total distance, probe test); unexposed animals improved over the course of acquisition trials, but their mean performance remained below that of the EE group. Enriched environment abrogated tau propagation and hippocampal tangle formation in the 600 ng group; in the 900 ng group, tangle formation was ∼10-fold of the 600 ng group, and unaffected by EE. CONCLUSION: Even a small difference in the amount of injected human AD tau can cause a pronounced difference in the number of resulting tangles. EE leads to a noticeably better spatial navigation performance of tau-injected animals. Furthermore, EE seems to be able to slow down tau pathology progression, indicating the possible utility of similar interventions in early stages of AD where tangle loads are still low.

Axon Neuroscience CRM Services SE Bratislava Slovakia

Axon Neuroscience R and D Services SE Bratislava Slovakia

Institute of Mathematics and Statistics Masaryk University Brno Czechia

Institute of Neuroimmunology Slovak Academy of Sciences Bratislava Slovakia

Neuroimunology Institute n p o Bratislava Slovakia

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Akwa Y., Gondard E., Mann A., Capetillo-Zarate E., Alberdi E., Matute C., et al. (2018). Synaptic activity protects against AD and FTD-like pathology PubMed DOI PMC

Albert M., Mairet-Coello G., Danis C., Lieger S., Caillierez R., Carrier S., et al. (2019). Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody. PubMed DOI PMC

Aoyagi A., Condello C., Stohr J., Yue W., Rivera B. M., Lee J. C., et al. (2019). Abeta and tau prion-like activities decline with longevity in the Alzheimer’s disease human brain. PubMed DOI PMC

Balietti M., Pugliese A., Conti F. (2021). In aged rats, differences in spatial learning and memory influence the response to late-life environmental enrichment. PubMed DOI

Balthazar J., Schowe N. M., Cipolli G. C., Buck H. S., Viel T. A. (2018). Enriched environment significantly reduced senile plaques in a transgenic mice model of Alzheimer’s disease, improving memory. PubMed DOI PMC

Boluda S., Iba M., Zhang B., Raible K. M., Lee V. M., Trojanowski J. Q. (2015). Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. PubMed PMC

Brundin P., Melki R., Kopito R. (2010). Prion-like transmission of protein aggregates in neurodegenerative diseases. PubMed PMC

Clavaguera F., Bolmont T., Crowther R. A., Abramowski D., Frank S., Probst A., et al. (2009). Transmission and spreading of tauopathy in transgenic mouse brain. PubMed PMC

Dong S., Li C., Wu P., Tsien J. Z., Hu Y. (2007). Environment enrichment rescues the neurodegenerative phenotypes in presenilins-deficient mice. PubMed DOI

Dosunmu R., Wu J., Basha M. R., Zawia N. H. (2007). Environmental and dietary risk factors in Alzheimer’s disease. PubMed

Fordyce D. E., Wehner J. M. (1993). Physical activity enhances spatial learning performance with an associated alteration in hippocampal protein kinase C activity in C57BL/6 and DBA/2 mice. PubMed

Franzmeier N., Neitzel J., Rubinski A., Smith R., Strandberg O., Ossenkoppele R., et al. (2020). Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease. PubMed PMC

Friedland R. P., Fritsch T., Smyth K. A., Koss E., Lerner A. J., Chen C. H., et al. (2001). Patients with Alzheimer’s disease have reduced activities in midlife compared with healthy control-group members. PubMed DOI PMC

Frost B., Diamond M. I. (2010). Prion-like mechanisms in neurodegenerative diseases. PubMed PMC

Gerenu G., Dobarro M., Ramirez M. J., Gil-Bea F. J. (2013). Early cognitive stimulation compensates for memory and pathological changes in Tg2576 mice. PubMed

Goedert M., Klug A., Crowther R. A. (2006). Tau protein, the paired helical filament and Alzheimer’s disease. PubMed

Held J. M., Gordon J., Gentile A. M. (1985). Environmental influences on locomotor recovery following cortical lesions in rats. PubMed

Huttenrauch M., Walter S., Kaufmann M., Weggen S., Wirths O. (2017). Limited effects of prolonged environmental enrichment on the pathology of 5XFAD mice. PubMed DOI

Jadhav S., Katina S., Kovac A., Kazmerova Z., Novak M., Zilka N. (2015). Truncated tau deregulates synaptic markers in rat model for human tauopathy. PubMed DOI PMC

Jankowsky J. L., Melnikova T., Fadale D. J., Xu G. M., Slunt H. H., Gonzales V., et al. (2005). Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer’s disease. PubMed DOI PMC

Jankowsky J. L., Xu G., Fromholt D., Gonzales V., Borchelt D. R. (2003). Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease. PubMed DOI

Jucker M., Walker L. C. (2013). Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. PubMed PMC

Karssemeijer E. G. A., Aaronson J. A., Bossers W. J. R., Donders R., Olde Rikkert M. G. M., Kessels R. P. C. (2019). The quest for synergy between physical exercise and cognitive stimulation PubMed DOI PMC

Kazlauckas V., Pagnussat N., Mioranzza S., Kalinine E., Nunes F., Pettenuzzo L., et al. (2011). Enriched environment effects on behavior, memory and BDNF in low and high exploratory mice. PubMed DOI

Kobayashi S., Ohashi Y., Ando S. (2002). Effects of enriched environments with different durations and starting times on learning capacity during aging in rats assessed by a refined procedure of the Hebb-Williams maze task. PubMed DOI

Koson P., Zilka N., Kovac A., Kovacech B., Korenova M., Filipcik P., et al. (2008). Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load. PubMed

La Joie R., Visani A. V., Baker S. L., Brown J. A., Bourakova V., Cha J., et al. (2020). Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET. PubMed DOI PMC

Laviola G., Hannan A. J., Macri S., Solinas M., Jaber M. (2008). Effects of enriched environment on animal models of neurodegenerative diseases and psychiatric disorders. PubMed

Lazarov O., Robinson J., Tang Y. P., Hairston I. S., Korade-Mirnics Z., Lee V. M., et al. (2005). Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. PubMed

Li B. Y., Wang Y., Tang H. D., Chen S. D. (2017). The role of cognitive activity in cognition protection: from bedside to bench. PubMed DOI PMC

Lopez-Ortiz S., Pinto-Fraga J., Valenzuela P. L., Martín-Hernández J., Seisdedos M. M., García-López O., et al. (2021). Physical exercise and Alzheimer’s disease: effects on pathophysiological molecular pathways of the disease. PubMed DOI PMC

Majerova P., Zilkova M., Kazmerova Z., Kovac A., Paholikova K., Kovacech B., et al. (2014). Microglia display modest phagocytic capacity for extracellular tau oligomers. PubMed DOI PMC

Montarolo F., Parolisi R., Hoxha E., Boda E., Tempia F. (2013). Early enriched environment exposure protects spatial memory and accelerates amyloid plaque formation in APP(Swe)/PS1(L166P) mice. PubMed DOI PMC

Morris R. G., Garrud P., Rawlins J. N., O’Keefe J. (1982). Place navigation impaired in rats with hippocampal lesions. PubMed

Mudher A., Colin M., Dujardin S., Medina M., Dewachter I., Naini S. M. A., et al. (2017). What is the evidence that tau pathology spreads through prion-like propagation? PubMed PMC

Nakano M., Kubota K., Hashizume S., Kobayashi E., Chikenji T. S., Saito Y., et al. (2020). An enriched environment prevents cognitive impairment in an Alzheimer’s disease model by enhancing the secretion of exosomal microRNA-146a from the choroid plexus. PubMed DOI PMC

Narasimhan S., Guo J. L., Changolkar L., Stieber A., McBride J. D., Silva L. V., et al. (2017). Pathological tau strains from human brains recapitulate the diversity of tauopathies in nontransgenic mouse brain. PubMed DOI PMC

Nelson P. T., Alafuzoff I., Bigio E. H., Bouras C., Braak H., Cairns N. J., et al. (2012). Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. PubMed DOI PMC

Ngandu T., Lehtisalo J., Solomon A., Levälahti E., Ahtiluoto S., Antikainen R., et al. (2015). A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. PubMed DOI

Nies S. H., Takahashi H., Herber C. S., Huttner A., Chase A., Strittmatter S. M. (2021). Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-beta. PubMed DOI PMC

Novak M., Kabat J., Wischik C. M. (1993). Molecular characterization of the minimal protease resistant tau unit of the Alzheimer’s disease paired helical filament. PubMed DOI PMC

Novati A., Nguyen H. P., Schulze-Hentrich J. (2022). Environmental stimulation in Huntington disease patients and animal models. PubMed

Orru C. D., Yuan J., Appleby B. S., Li B., Li Y., Winner D., et al. (2017). Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease. PubMed DOI PMC

Paxinos G., Watson C. (1997). PubMed

Pinheiro J. C., Bates D. M. (2006).

R Core Team (2022).

Ruthirakuhan M., Luedke A. C., Tam A., Goel A., Kurji A., Garcia A. (2012). Use of physical and intellectual activities and socialization in the management of cognitive decline of aging and in dementia: a review. PubMed PMC

Scholl M., Lockhart S. N., Schonhaut D. R., O’Neil J. P., Janabi M., Ossenkoppele R., et al. (2016). PET imaging of tau deposition in the aging human brain. PubMed PMC

Singhal G., Jaehne E. J., Corrigan F., Baune B. T. (2014). Cellular and molecular mechanisms of immunomodulation in the brain through environmental enrichment. PubMed DOI PMC

Smolek T., Cubinkova V., Brezovakova V., Valachova B., Szalay P., Zilka N., et al. (2019a). Genetic background influences the propagation of tau pathology in transgenic rodent models of tauopathy. PubMed DOI PMC

Smolek T., Jadhav S., Brezovakova V., Cubinkova V., Valachova B., Novak P., et al. (2019b). First-in-rat study of human Alzheimer’s disease tau propagation. PubMed DOI

Stephen R., Barbera M., Peters R., Ee N., Zheng L., Lehtisalo J., et al. (2021). Development of the first WHO guidelines for risk reduction of cognitive decline and dementia: lessons learned and future directions. PubMed DOI PMC

Stozicka Z., Korenova M., Uhrinova I., Cubinkova V., Cente M., Kovacech B., et al. (2020). Environmental enrichment rescues functional deficit and alters neuroinflammation in a transgenic model of tauopathy. PubMed DOI

Tanzi R. E. (2012). The genetics of Alzheimer disease. PubMed DOI PMC

Tanzi R. E. (2013). A brief history of Alzheimer’s disease gene discovery. PubMed

Urakawa S., Hida H., Masuda T., Misumi S., Kim T. S., Nishino H. (2007). Environmental enrichment brings a beneficial effect on beam walking and enhances the migration of doublecortin-positive cells following striatal lesions in rats. PubMed DOI

Valero J., Espana J., Parra-Damas A., Martin E., Rodriguez-Alvarez J., Saura C. A. (2011). Short-term environmental enrichment rescues adult neurogenesis and memory deficits in APP PubMed DOI PMC

van Dellen A., Blakemore C., Deacon R., York D., Hannan A. J. (2000). Delaying the onset of Huntington’s in mice. PubMed

Vorhees C. V., Williams M. T. (2006). Morris water maze: procedures for assessing spatial and related forms of learning and memory. PubMed PMC

Walker L. C., Jucker M. (2015). Neurodegenerative diseases: expanding the prion concept. PubMed PMC

Welch B. L. (1947). The generalization of ‘student’s’ problem when several different population variances are involved. PubMed

Wilson R. S., Mendes De Leon C. F., Barnes L. L., Schneider J. A., Bienias J. L., Evans D. A., et al. (2002). Participation in cognitively stimulating activities and risk of incident Alzheimer disease. PubMed

Wolf S. A., Kronenberg G., Lehmann K., Blankenship A., Overall R., Staufenbiel M., et al. (2006). Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer’s disease. PubMed DOI

Yamada K., Holth J. K., Liao F., Stewart F. R., Mahan T. E., Jiang H., et al. (2014). Neuronal activity regulates extracellular tau PubMed DOI PMC

Yu F., Rose K. M., Burgener S. C., Cunningham C., Buettner L. L., Beattie E., et al. (2009). Cognitive training for early-stage Alzheimer’s disease and dementia. PubMed

Ziegler-Waldkirch S., d’Errico P., Sauer J. F., Erny D., Savanthrapadian S., Loreth D., et al. (2018). Seed-induced Abeta deposition is modulated by microglia under environmental enrichment in a mouse model of Alzheimer’s disease. PubMed DOI PMC

Zilka N., Filipcik P., Koson P., Fialova L., Skrabana R., Zilkova M., et al. (2006). Truncated tau from sporadic Alzheimer’s disease suffices to drive neurofibrillary degeneration PubMed DOI

TLR4-mediated chronic neuroinflammation has no effect on tangle pathology in a tauopathy mouse model

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