Abstract
Alzheimer's disease (AD), the most common cause of dementia, is also associated with depression. Although the precise mechanisms that lead to depression in AD are unknown, the impairments in adult hippocampal neurogenesis observed in AD may play a role. Adult-born neurons play a critical role in regulating both cognition and mood, and reduced hippocampal neurogenesis is associated with depression in other neurological disorders. To assess the relationship between Alzheimer's disease, neurogenesis, and depression, we studied human amyloid precursor protein (hAPP) transgenic mice, a well-characterized model of AD. We report that reductions in hippocampal neurogenesis are evident early in disease progression in hAPP mice, but a mild depressive phenotype manifests only in later stages of disease. We found that hAPP mice exhibited a reduction in BrdU-positive cells in the subgranular zone of the dentate gyrus in the hippocampus, as well as a reduction in doublecortin-expressing cells, relative to nontransgenic controls at 5–7 months of age. These alterations in neurogenesis appeared to worsen with age, as the magnitude of reduction in doublecortin-expressing cells was greater in hAPP mice at 13–15 months of age. Only 13–15 month old hAPP mice exhibited depressive behavior in the tail suspension test. However, mice at both age groups exhibited deficits in spatial memory, which was observed in the Morris water maze test for hippocampus-dependent memory. These findings indicate that neurogenesis impairments are accompanied by cognitive deficits, but are not tightly linked to depressive behavior in hAPP mice.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by prominent impairments in memory [1]
G, Analysis of the first three minutes of the tail suspension test at baseline and at the 24 hr trial confirms that NTG, but not human amyloid precursor protein (hAPP), mice increase the time spent immobile upon repeated testing. n = 12/genotype (A–C) and n = 24/genotype (D–E). **p,0.01, ***p,0.001. doi:10.1371/journal.pone.0079651.g002
We demonstrate that hAPP mice exhibit significant impairments in neurogenesis by 5–7 months of age that worsen with age, but subtle depressive behavior in the tail suspension test is only measurable by 13–15 months of age
Summary
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by prominent impairments in memory [1]. Smaller Ab oligomers disrupt neuronal function early in disease progression, before plaques begin to form in mouse models of AD [3,4]. Neurogenesis is altered early in disease progression, prior to plaque deposition in AD mouse models, suggesting that it could play a role in early cognitive and/or psychiatric symptoms of AD [5,6,7,8]. The hippocampus is critical for learning and memory as well as mood regulation, and adult neurogenesis is necessary for normal function [9,10,11]. A number of reports have demonstrated that adult neurogenesis is altered in AD patients as well as mouse models; both increases and decreases in neurogenesis have been reported which may reflect different stages of disease [5,6,7,14]
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