Environmental Enrichment Rescues Functional Deficit and Alters Neuroinflammation in a Transgenic Model of Tauopathy

Article type: Research Article

Authors: Stozicka, Zuzana^{a; 1} | Korenova, Miroslava^{a; 1} | Uhrinova, Ivana^a | Cubinkova, Veronika^a | Cente, Martin^a | Kovacech, Branislav^{a; b} | Babindakova, Nikoleta^a | Matyasova, Katarina^a | Vargova, Greta^a | Novak, Michal^{a; c} | Novak, Petr^{a; d} | Zilka, Norbert^{a; b} | Jadhav, Santosh^{a; b; *}

Affiliations: [a] Institute of Neuroimmunology, Slovak Academy of Sciences, AD Centre, Bratislava, Slovakia | [b] Axon Neuroscience R&D Services SE, Bratislava, Slovakia | [c] Axon Neuroscience SE, Larnaca, Cyprus | [d] Axon Neuroscience CRM Services SE, Bratislava, Slovakia

Correspondence: [*] Correspondence to: Santosh Jadhav, Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska Cesta 9, 845 10 Bratislava, Slovakia. Tel.: +00412 2 5478 8100; Fax: +00412 2 5477 4276; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder, affecting over 44 million people worldwide. There are no effective pharmaco-therapeutic options for prevention and treatment of AD. Non-pharmacological approaches may help patients suffering from AD to significantly ameliorate disease progression. In this study, we exposed a transgenic rat model (tg) of human tauopathy to enriched environment for 3 months. Behavioral testing at 6 months of age revealed improvement in functional deficits of tg rats reared under enriched conditions, while sedentary tg rats remained severely impaired. Interestingly, enriched environment did not reduce tau pathology. Analysis of neurotrophic factors revealed an increase of nerve growth factor (NGF) levels in the hippocampus of both enriched groups (tg and non-tg rats), reflecting a known effect of enriched environment on the hippocampal formation. On the contrary, NGF levels decreased markedly in the brainstem of enriched groups. The non-pharmacological treatment also reduced levels of tissue inhibitor of metalloproteinase 1 in the brainstem of transgenic rats. Expression analysis of inflammatory pathways revealed upregulation of microglial markers, such as MHC class II and Cd74, whereas levels of pro-inflammatory cytokines remained unaffected by enriched environment. Our results demonstrate that exposure to enriched environment can rescue functional impairment in tau transgenic rats without reducing tau pathology. We speculate that non-pharmacological treatment modulates the immune response to pathological tau protein inclusions, and thus reduces the damage caused by neuroinflammation.

Keywords: Enriched environment, nerve growth factor, neuroinflammation, non-pharmacological intervention, tauopathy

DOI: 10.3233/JAD-191112

Journal: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 951-964, 2020