TY - JOUR
T1 - 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
AU - von Linstow, Christian Ulrich
AU - Waider, Jonas
AU - Bergh, Marianne Skov-Skov
AU - Anzalone, Marco
AU - Madsen, Cecilie
AU - Nicolau, Aina Battle
AU - Wirenfeldt, Martin
AU - Lesch, Klaus-Peter
AU - Finsen, Bente
N1 - Funding Information:
The authors would like to acknowledge Athana-sios Metaxas for assisting in dissections of tissue, Maiken Lyhne Kristensen is acknowledged for assistance with the mouse breeding, Sussanne Petersen for genotyping, assistance with histology, and for performing the mesoscale analysis, and Janne Skalshøj and Mohammad Talal Qasem for assisting in cutting brain material and performing immune stainings. The study was supported by the Danish Council for Independent Research, Fonden til Lægevidenskabens Fremme, The Velux Foundation, A.J. Andersens og Hustrus Fond, Torben og Alice Frimodts Fond, The Lundbeck Foundation, and by SDU2020, a fund created by the University of Southern Denmark.
Publisher Copyright:
© 2022 - IOS Press. All rights reserved.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - 5-HT
KW - 5-HT4 RECEPTOR
KW - A beta PP processing
KW - APP/PS1
KW - Alzheimer's disease
KW - BETA LEVELS
KW - DEMENTIA
KW - DEPLETION
KW - FLUID
KW - METABOLISM
KW - MICE
KW - MICROGLIA
KW - NEURONS
KW - PATHOLOGY
KW - cerebral amyloidosis
KW - cerebrospinal fluid
KW - neuroinflammation
KW - tryptophan hydroxylase 2
U2 - 10.3233/JAD-210581
DO - 10.3233/JAD-210581
M3 - Article
C2 - 34924373
SN - 1387-2877
VL - 85
SP - 1283
EP - 1300
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 3
ER -