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Changes in Astroglial Water Flow in the Pre-amyloid Phase of the STZ Model of AD Dementia

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Abstract

Alzheimer’s disease (AD) is an age-dependent neurodegenerative disease that is typically sporadic and has a high social and economic cost. We utilized the intracerebroventricular administration of streptozotocin (STZ), an established preclinical model for sporadic AD, to investigate hippocampal astroglial changes during the first 4 weeks post-STZ, a period during which amyloid deposition has yet to occur. Astroglial proteins aquaporin 4 (AQP-4) and connexin-43 (Cx-43) were evaluated, as well as claudins, which are tight junction (TJ) proteins in brain barriers, to try to identify changes in the glymphatic system and brain barrier during the pre-amyloid phase. Glial commitment, glucose hypometabolism and cognitive impairment were characterized during this phase. Astroglial involvement was confirmed by an increase in glial fibrillary acidic protein (GFAP); concurrent proteolysis was also observed, possibly mediated by calpain. Levels of AQP-4 and Cx-43 were elevated in the fourth week post-STZ, possibly accelerating the clearance of extracellular proteins, since these proteins actively participate in the glymphatic system. Moreover, although we did not see a functional disruption of the blood-brain barrier (BBB) at this time, claudin 5 (present in the TJ of the BBB) and claudin 2 (present in the TJ of the blood-cerebrospinal fluid barrier) were reduced. Taken together, data support a role for astrocytes in STZ brain damage, and suggest that astroglial dysfunction accompanies or precedes neuronal damage in AD.

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Funding

This research was supported by Conselho Nacional de Desenvolvimento Científico Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, PPSUS 21/2551-0000067-8) and Instituto Nacional de Ciência e Tecnologia (INCT) para Saúde Cerebral (406020/2022-1).

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  1. Vitor Gayger-Dias and Leonardo Menezes Contributed equivalently

Authors and Affiliations

  1. Biochemistry Laboratory 33, Graduate Program in Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos Street, 2600, Porto Alegre, 90035-003, Brazil

    Vitor Gayger-Dias, Leonardo Menezes, Vanessa-Fernanda Da Silva, Amanda Stiborski, Ana Carolina Ribeiro Silva, Thomas Michel Sobottka, Vitória Cristine Quines-Silva, Betina Pakulski-Souto, Larissa Daniele Bobermin, André Quincozes-Santos, Marina Concli Leite & Carlos-Alberto Gonçalves

  2. Graduate Program in Neurosciences, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos Street, 2600, Porto Alegre, 90035-003, Brazil

    Larissa Daniele Bobermin, André Quincozes-Santos & Carlos-Alberto Gonçalves

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Contributions

V.G.D., L.M., V.F.S. and C.A.G. conceptualized the study. V.G.D., L.M., V.F.S., A.S., A.C.R.S., T.M.S., V.C.Q.S. and B.P.S. performed the experiments. V.G.D. and V.F.S. performed statistical analysis. C.A.G., V.G.D. and L.M. wrote the original draft of the manuscript. C.A.G., M.C.L., L.D.B. and A.Q.S. provided materials and laboratory facilities. All authors revised, edited, and approved the manuscript.

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Correspondence to Carlos-Alberto Gonçalves.

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This study protocol was reviewed and approved by the Animal Care and Use Committee of the Universidade Federal do Rio Grande do Sul, approval number 37479.

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Gayger-Dias, V., Menezes, L., Da Silva, VF. et al. Changes in Astroglial Water Flow in the Pre-amyloid Phase of the STZ Model of AD Dementia. Neurochem Res (2024). https://doi.org/10.1007/s11064-024-04144-6

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