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

Stozicka, Zuzana; Korenova, Miroslava; Uhrinova, Ivana; Cubinkova, Veronika; Cente, Martin; Kováčech, Branislav; Babindakova, Nikoleta; Matyasova, Katarina; Vargová, Gréta; Novák, Michal; Novák, Petr; Žilka, Norbert; Jadhav, Santosh

doi:10.3233/jad-191112

Cited by 4 publications

(5 citation statements)

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“…Coincidentally, one of the first animal studies came from Huntington disease transgenic animals ( van Dellen et al, 2000 ), and later ones from other neurodegenerative disorders such as Alzheimer’s disease or Parkinson’s disease ( Laviola et al, 2008 ), supporting this notion. A positive impact of EE on motor functions was also observed in animals with motor deficits, specifically 6-OHDA lesioned rats ( Urakawa et al, 2007 ) and tau-transgenic rats with progressive brainstem pathology ( Stozicka et al, 2020 ). The latter study is especially relevant, as it shows that EE can ameliorate deficits caused by continuously accruing tau pathology, whereas EE in toxic lesion models is more akin to rehabilitation after one-time injury.…”

Section: Discussionmentioning

confidence: 93%

“…Our previous study on the impacts of EE in the utilized SHR72 transgenic rats showed upregulated expression of microglial/macrophage markers Rt1-Ba, CD74, and Gpnmb, associated with increased number/overstimulation of microglia, or increased influx of blood-born monocytes into the brain. With Rt1-Ba and CD74 being responsible for antigen processing and increased phagocytic activity of microglia, and Gpnmb inhibiting certain activities of microglia/macrophages via negative regulation of pro-inflammatory molecules, this indicates a pronounced shift of microglial activity toward phagocytosis and protein clearance ( Stozicka et al, 2020 ). Thus, modulation of immune function via EE ( Singhal et al, 2014 ) could allow neurons to ‘outsource’ a part of the processing of pathological tau to immune cells.…”

Section: Discussionmentioning

confidence: 99%

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Enriched environment ameliorates propagation of tau pathology and improves cognition in rat model of tauopathy

Mate

Smolek

Kazmerova

et al. 2022

Front. Aging Neurosci.

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IntroductionThe 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.MethodsWe 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.ResultsAnimals 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.ConclusionEven 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.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Enriched environment ameliorates propagation of tau pathology and improves cognition in rat model of tauopathy

Mate

Smolek

Kazmerova

et al. 2022

Front. Aging Neurosci.

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“…A number of studies have shown that EE produces rather mild or mixed results, especially during the later stages of AD pathology. These findings include failing to reduce Aβ or tau pathology, cognitive decline, or neuronal loss, and not improving cognitive performance, inflammation levels, or neurogenesis [95][96][97][98][99][100][101][102][103][104][105][106]. These works have not necessarily been unsuccessful in demonstrating some improvements following EE, but the effects are not as robust as the studies discussed above.…”

Section: Roles Of Enrichment In Animal Models Of Alzheimer's Diseasementioning

confidence: 95%

“…Did not influence ptau [102] APP sw (both sexes-mouse) Increased spatial memory despite continued Aβ deposition [103] PDAPP-J20 (female-mouse) Reduced Aβ Improved astroglial response toward plaques [104] 3xTg-AD (both sexes-mouse) Mild improvements to spatial learning in advanced stages [105] SHR72 (male-rat) Increased spatial memory performance Reduced ptau in mild cases [106] APP swe /PS1 Environmental Enrichment with Donepezil Aβ1-42 infusion at hippocampus (male-rat)…”

Section: Improved Motor Skills Mildly Improved Inflammationmentioning

confidence: 99%

Life Experience Matters: Enrichment and Stress Can Influence the Likelihood of Developing Alzheimer’s Disease via Gut Microbiome

et al. 2023

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Alzheimer’s disease (AD) is a chronic neurodegenerative disease, characterized by the presence of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) formed from abnormally phosphorylated tau proteins (ptau). To date, there is no cure for AD. Earlier therapeutic efforts have focused on the clinical stages of AD. Despite paramount efforts and costs, pharmaceutical interventions including antibody therapies targeting Aβ have largely failed. This highlights the need to alternate treatment strategies and a shift of focus to early pre-clinical stages. Approximately 25–40% of AD cases can be attributed to environmental factors including chronic stress. Gut dysbiosis has been associated with stress and the pathogenesis of AD and can increase both Aβ and NFTs in animal models of the disease. Both stress and enrichment have been shown to alter AD progression and gut health. Targeting stress-induced gut dysbiosis through probiotic supplementation could provide a promising intervention to delay disease progression. In this review, we discuss the effects of stress, enrichment, and gut dysbiosis in AD models and the promising evidence from probiotic intervention studies.

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“…It has been found that H2-Ob is up-regulated in Niemann-Pick disease type C and multiple sclerosis, two neurodegenerative disorders [ 19 , 20 ]. Moreover, a recent study showed that the expression levels of MHC class II molecules were increased in a transgenic rat model of human tauopathy [ 21 ]. Furthermore, using a computational model, we previously suggested that the H2-Ob gene might regulate the co-expression relationship of two genes Csf1r and Milr1 , possibly being involved in AD [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

RT-DOb, a switch gene for the gene pair {Csf1r, Milr1}, can influence the onset of Alzheimer’s disease by regulating communication between mast cell and microglia

et al. 2023

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In biology, homeostasis is a central cellular phenomenon that plays a crucial role in survival. The central nervous system (CNS) is controlled by exquisitely sensitive homeostatic mechanisms when facing inflammatory or pathological insults. Mast cells and microglia play a crucial role in CNS homeostasis by eliminating damaged or unnecessary neurons and synapses. Therefore, decoding molecular circuits that regulate CNS homeostasis may lead to more effective therapeutic strategies that specifically target particular subsets for better therapy of Alzheimer’s disease (AD). Based on a computational analysis of a microarray dataset related to AD, the H2-Ob gene was previously identified as a potential modulator of the homeostatic balance between mast cells and microglia. Specifically, it plays such a role in the presence of a three-way gene interaction in which the H2-Ob gene acts as a switch in the co-expression relationship of two genes, Csf1r and Milr1. Therefore, the importance of the H2-Ob gene as a potential therapeutic target for AD has led us to experimentally validate this relationship using the quantitative real-time PCR technique. In the experimental investigation, we confirmed that a change in the expression levels of the RT1-DOb gene (the rat ortholog of murine H2-Ob) can switch the co-expression relationship between Csf1r and Milr1. Furthermore, since the RT1-DOb gene is up-regulated in AD, the mentioned triplets might be related to triggering AD.

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

Cited by 4 publications

References 48 publications

Enriched environment ameliorates propagation of tau pathology and improves cognition in rat model of tauopathy

Enriched environment ameliorates propagation of tau pathology and improves cognition in rat model of tauopathy

Life Experience Matters: Enrichment and Stress Can Influence the Likelihood of Developing Alzheimer’s Disease via Gut Microbiome

RT-DOb, a switch gene for the gene pair {Csf1r, Milr1}, can influence the onset of Alzheimer’s disease by regulating communication between mast cell and microglia

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