| First Author | von Linstow CU | Year | 2022 |
| Journal | J Alzheimers Dis | Volume | 85 |
| Issue | 3 | Pages | 1283-1300 |
| PubMed ID | 34924373 | Mgi Jnum | J:350984 |
| Mgi Id | MGI:7664661 | Doi | 10.3233/JAD-210581 |
| Citation | von Linstow CU, et al. (2022) 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. J Alzheimers Dis 85(3):1283-1300 |
| abstractText | 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-beta (Abeta). 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) DeltaE9 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 Abeta42/40/38, soluble APPalpha (sAbetaPPalpha) and sAbetaPPbeta, and cytokines were analyzed by mesoscale, neurotransmitters by mass spectrometry, and gene expression by quantitative PCR. Tph2, microglia, and Abeta were visualized histologically. RESULTS: Tph2 inactivation in APP/PS1 mice significantly reduced viability, without impacting soluble and insoluble Abeta42 and Abeta40 in neocortex and hippocampus, and with only mild changes of soluble Abeta42/Abeta40. However, sAbetaPPalpha and sAbetaPPbeta in hippocampus and Abeta38 and Abeta40 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 Abeta plaques regardless of genotype. CONCLUSION: The results suggest that Tph2 inactivation influences AbetaPP processing, at least in the hippocampus, although levels of Abeta 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. |
