Early postnatal handling reduces hippocampal amyloid plaque formation and enhances cognitive performance in APPswe/PS1dE9 mice at middle age

Highlights

• Early handling (EH) leads to enhanced maternal care.

• In APPswe/PS1dE9 mice, EH reduces hippocampal but not amygdala plaque pathology.

• EH delays working and emotional memory deficits in APPswe/PS1dE9 mice.

Abstract

In rodents, fragmented and low levels of maternal care have been implicated in age-related cognitive decline and the incidence and progression of Alzheimer's pathology. In contrast, enhancing early postnatal maternal care has been associated with improved cognitive function later in life. Here we examined whether early postnatal handling of mouse pups from postnatal days 2–9 enhanced maternal care and whether this affected cognition and Alzheimer pathology at 5 and 11 months of age in the APPswe/PS1dE9 mouse model for Alzheimer’s disease.

Brief, 15 min daily episodes of separating offspring from their dams from postnatal days 2–9 (early handling, EH) increased maternal care of the dam towards her pups upon reunion. At 11 (but not 5) months of age, EH APPswe/PS1dE1 mice displayed significantly reduced amyloid plaque pathology in the hippocampus. At this age, EH also prevented short-term working memory deficits while restoring impairments in contextual fear memory formation in APPswe/PS1dE9 mice. EH did not modulate amyloid pathology in the amygdala, nor did it affect auditory fear conditioning deficits in APPswe/PS1dE9 mice.

We conclude that increased levels of maternal care during the early life period delays amyloid accumulation and cognitive decline in an Alzheimer’s mouse model, involving the hippocampus, but not to the amygdala. These studies highlight the importance of the early postnatal period in modulating resilience to develop Alzheimer’s pathology later in life.

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by progressive impairments in cognitive and emotional functioning (Selkoe & Schenk, 2003). Prominent neuropathological features of AD are amyloid-containing plaques and neurofibrillary tangles, which are present in brain areas critical for memory formation and emotion regulation, such as the hippocampus and amygdala (Braak & Braak, 1996).

While genetic mutations are associated with rare familial variants of AD, the vast majority of AD cases are sporadic and have no genetic cause. Epidemiological studies have shown that lifestyle factors are important for the incidence and progression of AD (Fratiglioni and Qiu, 2009, Gates and Valenzuela, 2010, Le Coutre et al., 2013, Papp et al., 2009). For example, stress exposure has been associated with an increased incidence of AD and AD pathology in humans and rodents (Aznar and Knudsen, 2011, Csernansky et al., 2006, Green et al., 2006, Hoogendijk et al., 2006, Huang et al., 2009, Lee et al., 2009, Mejía et al., 2003). In rodents, environmental stimulation has been reported to improve learning and memory later in life, and to protect from brain pathology (Arendash et al., 2004, Faherty et al., 2005, Gage et al., 1999, Hockly et al., 2002, Jadavji et al., 2006, Jankowsky et al., 2003, Lazarov et al., 2005, Pang and Hannan, 2013, Papp et al., 2009, Rampon et al., 2000, Redolat and Mesa-Gresa, 2011, Spires et al., 2004, van Dellen et al., 2000).

Exposure to environmental enrichment has particularly strong and long-lasting effects on cognition during the early postnatal period, i.e. when the brain is still developing. For instance, early handling (EH), which involves the separation of the dam and offspring for 15 min per day during at least the first week of life, produces a variety of long-term neuro-behavioural effects. Later in life, EH e.g. reduces conditioned and unconditioned fear and anxiety (Fernández-Teruel et al., 1997, Levine et al., 1956, Núñez et al., 1996), blunts behavioural and endocrine sensitivity to stressors (Meaney et al., 1988, Núñez et al., 1996, Papaioannou et al., 2002), and reduces age-related cognitive decline in rodents (Meaney et al., 1988).

In the current study, we examined whether early life handling from postnatal days (PND) 2–9 modifies cognition and amyloid plaque pathology in the classic APPswe/PS1dE9 mouse model for AD (Jankowsky et al., 2001), both in young (5 months) and middle-aged (11 months) animals.