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

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 (A beta). 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)(Delta E9) 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 A beta(42/40/38), soluble APP beta (sA beta PP beta) and sA beta PP beta, and cytokines were analyzed by mesoscale, neurotransmitters by mass spectrometry, and gene expression by quantitative PCR. Tph2, microglia, and A beta were visualized histologically. Results: Tph2 inactivation in APP/PS1 mice significantly reduced viability, without impacting soluble and insoluble A beta(42) and A beta(40) in neocortex and hippocampus, and with only mild changes of soluble A beta(42)/A beta(40). However, sA beta PP alpha and sA beta PP beta in hippocampus and A beta(38) and A beta(40) 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, HTR2 alpha and HTR2 beta mRNA levels in Tph2-/- mice. Microglia clustered around A beta plaques regardless of genotype. Conclusion: The results suggest that Tph2 inactivation influences A beta PP processing, at least in the hippocampus, although levels of A beta 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.