Behavioral and neurobiological effects of prenatal stress exposure in male and female APPswe/PS1dE9 mice.
Epidemiological evidence implies a role for chronic stress and stress-related disorders in the etiopathogenesis of sporadic Alzheimer's disease (AD). Although chronic stress exposure during various stages of life has been shown to exacerbate AD-related cognitive deficits and neuropathology in AD mouse models, the role of stress exposure during the prenatal period on AD development and progression remained to be investigated. The present study therefore explored the effects of prenatal maternal stress (PMS) in both male and female APPswe/PS1dE9 mouse offspring in terms of cognition, affect, and AD-related neuropathology. As prenatal perturbations are likely to mediate their effects via alterations in epigenetic regulation, changes in hippocampal DNA methyltransferase 3a, 5-methylcytosine and 5-hydroxymethylcytosine levels were assessed as underlying mechanisms. Repetitive restraint stress during the first week of gestation exerted a sex-dependent effect, with male PMS mice showing spatial memory deficits and a blunted hypothalamus-pituitary-adrenal axis response, while female PMS mice showed improved spatial memory performance, increased depressive-like behavior, as well as a decrease in hippocampal plaque load. In addition, sex differences were observed among APPswe/PS1dE9 mice, independent of PMS (i.e., female mice showed impaired spatial memory performance, higher hippocampal plaque load, altered amyloid precursor protein processing in the CA3 and lower DNA methyltransferase 3a immunoreactivity in the dentate gyrus when compared with male mice of the same age). In conclusion, PMS exposure impacts on the behavioral phenotype and neuropathology of APPswe/PS1dE9 mice. Moreover, given the remarkable sex differences observed, one should not overlook the impact of sex-specific responses to environmental exposures when investigating gene-environment interactions in AD.
School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
Annerieke S R
AS
Sierksma
Jos
J
Prickaerts
Leonidas
L
Chouliaras
Somayeh
S
Rostamian
Lore
L
Delbroek
Bart P F
BP
Rutten
Harry W M
HW
Steinbusch
Daniel L A
DL
van den Hove
D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001526:Behavioral Symptoms / Q000209:etiology*; D001572:Benzofurans; D003072:Cognition Disorders / Q000209:etiology*; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000201:enzymology; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D053764:Presenilin-1 / Q000235:genetics; D011804:Quinolines; D013028:Space Perception / Q000502:physiology; D013315:Stress, Psychological / Q000150:complications* / Q000473:pathology
C576715:(3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide; D016564:Amyloid beta-Protein Precursor; D001572:Benzofurans; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011804:Quinolines; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A