Soluble βamyloid_1‐42: a critical player in producing behavioural and biochemical changes evoking depressive‐related state?

Abstract

Background and purpose: Depression is common in early phases of Alzheimer's disease (AD) and may represent prodromal symptoms of dementia. Recent reports suggest that early memory deficits and neuropsychiatric symptoms are caused by soluble rather than aggregated bamyloid (Ab). Thus, we investigated the effects of soluble Ab1-42 on working memory and depressive/anxiety-related behaviour in rats and on 5-hydroxytryptaminergic neurotransmission and neurotrophin content in various brain regions. Experimental approach: Behavioural reactivity to novel object recognition, open field, elevated plus maze and forced swimming test were assessed 7 days after i.c.v. injection of Ab1-42 or its vehicle. BDNF (brain-derived neurotrophic factor) and NGF (nerve growth factor) mRNA and protein levels and 5-hydroxytriptamine (5-HT) content were measured in the prefrontal cortex (PFC), striatum (STR) and nucleus accumbens (NAc). Key results: Ab1-42 did not affect the ability to distinguish between familiar and novel objects, but Ab-treated rats exhibited an increase in forced swimming immobility. No differences were revealed between experimental groups in the elevated plus maze test or in self-grooming (evaluated in the open field). In the PFC, but not STR or NAc, Ab-injected rats exhibited a selective reduction in 5-HT content, BDNF and NGF expression. Conclusions and implications: Our data suggest that soluble Ab-treated rats have a depressive, but not anxiogenic-like, profile, accompanied by brain region-dependent alterations in the expression of neurotrophins and 5-hydroxytryptaminergic neurotransmission. Hence, these alterations induced by soluble Ab might be sensitive indicators of early phases of AD and possible risk factors for the expression of neuropsychiatric symptoms in AD.

Cortical Amyloid β Deposition and Current Depressive Symptoms in Alzheimer Disease and Mild Cognitive Impairment

“…There is evidence of infusion of Aβ peptides inducing depressive-like behaviors in mice. 59,60 Although these were rodent studies, it is very important to investigate whether there is a bidirectional relationship between depressive symptoms and Aβ levels in humans. We did not look into the potential role of Aβ promoting depression, and future studies should investigate this relationship.…”

Amyloid Hypothesis: Is There a Role for Antiamyloid Treatment in Late-Life Depression?

“…Pro-inflammatory cytokines compromise neurogenesis, neural plasticity, neurotransmitter synthesis, and neuroendocrine function (42). In rats, intracerebrovascular administration of soluble Aβ 1–42 led to depression-like behavior in the forced swim test (13). It also led to reduction in the content of serotonin and the expression of brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF).…”

“…These abnormalities have been attributed to vascular compromise at least in a subgroup of depressed older patients (10–12). Several lines of evidence suggest that sustained elevations of beta-amyloid (Aβ) lead to brain abnormalities associated with depression (13, 14). …”

Plasma Amyloid-β Levels in Drug-Resistant Bipolar Depressed Patients Receiving Electroconvulsive Therapy

“…In rats, a BDNF pretreatment is able to prevent neuronal damage induced by Aβ injection [55], and a single i.v. Aβ injection was reported to induce a depressive phenotype and to inhibit BDNF expression in the prefrontal cortex [56]. Based on these observations, we speculate with caution that the altered plasma Aβ peptide levels of the resistant patients would reflect some brain neurodegenerative and neurotoxic phenomena hindering the BDNF-mediated neurorestorative action induced by ECT.…”