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Amyloid-β oligomers link depressive-like behavior and cognitive deficits in mice

Year: 2012

Type: article

Abstract: Depression is one of the most common psychiatric symptoms in Alzheimer’s disease (AD), and considerable evidence indicates that major depressive disorder increases the risk of AD. 1 , 2 , 3 To date, however, the molecular mechanisms underlying the clinical association between depression and AD have remained elusive. Soluble oligomers of the amyloid-β peptide (AβOs) accumulate in the brains of AD patients and are increasingly recognized as the proximal neurotoxins responsible for synapse failure and memory deficits in AD. 4 , 5 We have hypothesized that AβOs might be mechanistically linked to behavioral changes in AD. In order to test this hypothesis, mice were given a single intracerebroventricular (i.c.v.) injection of 10 pmol AβOs and were subsequently evaluated in the Porsolt forced swim test (FST) for assessment of depressive-like behavior. Compared with vehicle-injected control mice, AβO-injected mice exhibited a significant increase in immobility in the FST, both 24 h and 8 days after AβO injections ( Figure 1a ). Similar results were obtained when animals were assessed in the tail suspension test, another classical task to evaluate depressive-like behavior in rodents ( Supplementary Figure S1a ). AβO-induced immobility in the FST was blocked by anti-depressant (fluoxetine) treatment ( Figure 1a ). An important feature of depressive disorder is anhedonic behavior, including decreased interest for pleasurable sensorial experiences. Whereas vehicle-injected mice exhibited an expected preference for sucrose solution over plain water, AβO-injected mice did not exhibit such preference, indicating that AβOs instigate anhedonic behavior ( Figure 1b ). Figure 1 Amyloid-β oligomers (AβOs) induce depressive-like behavior, memory deficits and hippocampal recruitment of microglia and astrocytes in mice. Three-month-old Swiss mice received a single intracerebroventricular (i.c.v.) injection of AβOs (10 pmol) or vehicle, and were submitted to behavioral tests 24 h or 8 days after injection. ( a ) Immobility time (s) in the Porsolt forced swim test (FST) was measured for vehicle- and AβO-injected animals, treated with fluoxetine (Flx, 30 mg kg −1 ) or saline (Sal). Flx was administered 23 h, 5 h and 1 h before AβO injection. Bars represent means±s.e.m. * P <0.05, ** P <0.01; analysis of variance followed by post-hoc Newman–Keuls test ( n =7–10 mice per group). ( b ) Sucrose preference expressed as the ratio between the volumes of 2% sucrose solution or plain water consumed. Bars represent means±s.e.m. * P <0.05; Student’s one-sample t -test ( n =13–14 mice per group) compared with 1 (no preference). ( c ) Recognition memory was assessed using the novel object recognition (OR) task. The percentage of time spent exploring the old (familiar) or new (novel) objects was measured for animals injected with vehicle or AβOs, treated with Flx (10 mg kg −1 daily for 17 days) or saline (Sal). Bars represent means±s.e.m. * P <0.05, Student’s one-sample t -test ( n =8–11 mice per group). ( d , e ) Levels of pro-inflammatory cytokines (interleukin (IL)-1β and tumor necrosis factor (TNF)-α) in brain extracts from mice injected i.c.v. with AβOs or vehicle. Bars represent means±s.e.m. * P <0.05, ** P <0.01; Student’s t -test ( n =6–8 mice per group). ( f – o ) Microglia (Iba-1-positive cells) and astrocytes (GFAP-positive cells) in the hippocampus of mice injected i.c.v. with AβOs or vehicle, and treated with Sal or Flx. Scale bars=50 μm. Bars in panels j and o represent means±s.e.m. * P <0.05, *** P <0.001; analysis of variance followed by Bonferroni test ( n =3–6 mice per group). PowerPoint slide Full size image

Source: Molecular Psychiatry

DOI: 10.1038/mp.2012.168