Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice.
A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five-month-old male and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7-month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (Abeta) and numbers of Abeta immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model suggests that such drugs administered prophylactically might retard the development of AD in humans.
Nelson
Rhonda L
RL
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.
Guo
Zhihong
Z
Halagappa
Veerendra Madala
VM
Pearson
Michelle
M
Gray
Audrey J
AJ
Matsuoka
Yasuji
Y
Brown
Martin
M
Martin
Bronwen
B
Iyun
Titilola
T
Maudsley
Stuart
S
Clark
Robert F
RF
Mattson
Mark P
MP
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000523:psychology*; D000679:Amygdala / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D001523:Mental Disorders / Q000523:psychology*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D017374:Paroxetine / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013550:Swimming; D024801:Tauopathies / Q000517:prevention & control
D016229:Amyloid beta-Peptides; D017374:Paroxetine; D010446:Peptide Fragments; D017367:Selective Serotonin Reuptake Inhibitors; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)