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-4β (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 Aβ 42/40/38, 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 Aβ 42 and Aβ 40 in neocortex and hippocampus, and with only mild changes of soluble Aβ 42/Aβ 40. However, sAβPPα and sAβPPβ in hippocampus and Aβ 38 and Aβ 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, 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.

Treating Depression and other Serotonin Deficiency Brain Disorders with Tryptophan

: Deficits of brain serotonin (5-hydroxytryptamine; 5-HT) are implicated in a number of psychiatric illnesses including depression. Treatment efficacy of this highly prevalent brain disorder is not adequate largely because serotonin stores are depleted. Tryptophan an essential amino acid is the sole precursor of serotonin; its systemic or oral administration increases serotonin synthesis because tryptophan hydroxylase, the rate limiting enzyme of 5-HT biosynthesis, is physiologically unsaturated with its substrate. The present article targets importance of tryptophan supplementation in treating serotonin deficiency and improving therapeutic intervention in depression and other serotonin deficiency brain disorders.

Increase of 5-HT levels is induced both in mouse brain and HEK-293 cells following their exposure to a non-viral tryptophan hydroxylase construct

Tryptophan hydroxylase type 2 (Tph2) is the rate-limiting enzyme for serotonin (5-HT) biosynthesis in the brain. Dysfunctional Tph2 alters 5-HT biosynthesis, leading to a deficiency of 5-HT, which could have repercussions on human behavior. In the last decade, several studies have associated polymorphisms of the TPH2 gene with suicidal behavior. Additionally, a 5-HT deficiency has been implicated in various psychiatric pathologies, including alcoholism, impulsive behavior, anxiety, and depression. Therefore, the TPH2 gene could be an ideal target for analyzing the effects of a 5-HT deficiency on brain function. The aim of this study was to use the construct pIRES-hrGFP-1a-Tph2-FLAG to treat CD1-male mice and to transfect HEK-293-cells and then to evaluate whether this treatment increases 5-HT production. 5-HT levels were enhanced 48 h post-transfection, in HEK-293 cells. Three days after the ocular administration of pIRES-hrGFP-1a-Tph2-FLAG to mice, putative 5-HT production was significantly higher than in the control in both hypothalamus and amygdala, but not in the brainstem. Further research will be needed on the possible application of this treatment for psychiatric diseases involving a Tph2 dysfunction or serotonin deficiency.

Chemical imbalance and mental health

No chemical imbalances have been proven to exist in relation to any mental health condition, like serotonin deficiency in synapses in the so-called depressive disorders or dopamine imbalance and dopamine receptors distribution in socalled schizophrenia. No independent objective biological marker or current brain imagining science like fMRI exist to date in support of any psychiatric diagnosis, and finally yet importantly, no biological causes exist for any of the socalled psychiatric disorders. If we avoid Cartesian dualism, the claim that mental disorders are biological is obviously a tautology. Given the facts above, psychiatric diagnostic manuals, such as the DSM and ICD, are school examples of what evidence-based science is not and represent nothing but a failed attempt to build a legal road from Health Care to Hell Care by over-medicalization and by the suffering of human and non-human animals. Furthermore, psychiatric drugs can have long-lasting effects on the brain and the central nervous system, while, the withdrawal from them can cause a range of severe physical and psychological effects.

How Evidence-Based is Evidence-Biased Medicine

No chemical imbalances have been proven to exist in relation to any mental health condition, like serotonin deficiency in synapses in the socalled depressive disorders or dopamine imbalance and dopamine receptors distribution in so-called schizophrenia. No independent objective biological marker or current brain imagining science like fMRI exist to date in support of any psychiatric diagnosis, and finally yet importantly, no biological causes exist for any of the so-called psychiatric disorders. If we avoid Cartesian dualism, the claim that mental disorders are biological is obviously a tautology. Given the facts above, psychiatric diagnostic manuals, such as the DSM and ICD, are school examples of what evidence-based science is not and represent nothing but a failed attempt to build a legal road from Health Care to Hell Care by over-medicalization and by the suffering of human and non-human animals. Furthermore, psychiatric drugs can have long-lasting effects on the brain and the central nervous system, while the withdrawal from them can cause a range of severe physical and psychological effects.