The Combined Effects of Amyloidosis and Serotonin Deficiency by Tryptophan Hydroxylase-2 Knockout Impacts Viability of the APP/PS1 Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: von Linstow, Christian Ulrich^{a; b} | Waider, Jonas^c | Bergh, Marianne Skov-Skov^d | Anzalone, Marco^{a; e} | Madsen, Cecilie^{a; e} | Nicolau, Aina Battle^a | Wirenfeldt, Martin^{e; f} | Lesch, Klaus-Peter^{c; g; h} | Finsen, Bente^{a; e; *}

Affiliations: [a] Department of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark | [b] Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA | [c] Division of Molecular Psychiatry, Center of Mental Health, University of Wuerzburg, Würzburg, Germany | [d] Section for Drug Abuse Research, Department of Forensic Sciences, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway | [e] BRIDGE - Brain Research-Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense C, Denmark | [f] Department of Pathology, Institute of Clinical Science, Odense University Hospital, Denmark | [g] Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia | [h] Department of Neuropsychology and Psychiatry, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands

Correspondence: [*] Correspondence to: Bente Finsen, Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsløws Vej 25, DK-5000 Odense C, Denmark. E-mail: [email protected].

Abstract: Background:A decline of brain serotonin (5-HT) is held responsible for the changes in mood that can be observed in Alzheimer’s disease (AD). However, 5-HT’ergic signaling is also suggested to reduce the production of pathogenic amyloid-β (Aβ). Objective:To investigate the effect of targeted inactivation of tryptophan hydroxylase-2 (Tph2), which is essential for neuronal 5-HT synthesis, on amyloidosis in amyloid precursor protein (APP)swe/presenilin 1 (PS1) ΔE9 transgenic mice. Methods:Triple-transgenic (3xTg) APP/PS1 mice with partial (+/-) or complete Tph2 knockout (–/–) were allowed to survive until 6 months old with APP/PS1, Tph2–/–, and wildtype mice. Survival and weight were recorded. Levels of Aβ42/40/38, soluble APPα (sAβPPα) and sAβPPβ, and cytokines were analyzed by mesoscale, neurotransmitters by mass spectrometry, and gene expression by quantitative PCR. Tph2, microglia, and Aβ were visualized histologically. Results:Tph2 inactivation in APP/PS1 mice significantly reduced viability, without impacting soluble and insoluble Aβ42 and Aβ40 in neocortex and hippocampus, and with only mild changes of soluble Aβ42/Aβ40. However, sAβPPα and sAβPPβ in hippocampus and Aβ38 and Aβ40 in cerebrospinal fluid were reduced. 3xTg–/–mice were devoid of Tph2 immunopositive fibers and 5-HT. Cytokines were unaffected by genotype, as were neocortical TNF, HTR2a and HTR2b mRNA levels in Tph2–/– mice. Microglia clustered around Aβ plaques regardless of genotype. Conclusion:The results suggest that Tph2 inactivation influences AβPP processing, at least in the hippocampus, although levels of Aβ are unchanged. The reduced viability of 3xTg–/–mice could indicate that 5-HT protects against the seizures that can impact the viability of APP/PS1 mice.

Keywords: Alzheimer’s disease, APP/PS1, AβPP processing, cerebral amyloidosis, cerebrospinal fluid, 5-HT, neuroinflammation, tryptophan hydroxylase 2

DOI: 10.3233/JAD-210581

Journal: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1283-1300, 2022