Abstract
Apolipoprotein E (APOE) effects on brain function remain controversial. Removal of APOE not only impairs cognitive functions but also reduces neuritic amyloid plaques in mouse models of Alzheimer's disease (AD). Can APOE simultaneously protect and impair neural circuits? Here, we dissociated the role of APOE in AD versus aging to determine its effects on neuronal function and synaptic integrity. Using two-photon calcium imaging in awake mice to record visually evoked responses, we found that genetic removal of APOE improved neuronal responses in adult APP/PSEN1 mice (8-10 mo). These animals also exhibited fewer neuritic plaques with less surrounding synapse loss, fewer neuritic dystrophies, and reactive glia. Surprisingly, the lack of APOE in aged mice (18-20 mo), even in the absence of amyloid, disrupted visually evoked responses. These results suggest a dissociation in APOE's role in AD versus aging: APOE may be neurotoxic during early stages of amyloid deposition, although being neuroprotective in latter stages of aging.
Highlights
Apolipoprotein E (APOE) in the central nervous system (CNS) has been the focus of study for two reasons: it is the most abundantly expressed apolipoprotein in the CNS (Bjorkhem & Meaney, 2004; Huang & Mahley, 2014), and inheritance of the E4 allele of the APOE gene profoundly impacts the risk for Alzheimer’s disease (AD), exacerbating amyloid deposition and worsening cognition and synapse loss
Neurons rely on cholesterol from glial cells for many processes; APOE plays an important role in modulating synapse growth, stabilization, and renewal in a physiological context (Holtzman & Fagan, 1998; Mauch et al, 2001)
APOE, the major apolipoprotein of the brain and most important genetic contributor to the sporadic form of AD (Wisniewski & Frangione, 1992; Corder et al, 1993, 1994; West et al, 1994; Hyman et al, 1996; Lippa et al, 1997), is a well-established partner of amyloid β peptides and has been shown to directly impact the aggregation, deposition, and clearance of those neurotoxic species (Holtzman et al, 2000; Fagan et al, 2002; Deane et al, 2008; Castellano et al, 2011; Hashimoto et al, 2012; Koffie et al, 2012; Hudry et al, 2013). Those findings clearly emphasize the pivotal role of APOE in AD neuropathological changes, the field is still divided as to whether or not clinical benefit could be achieved by reducing the levels of APOE (Koldamova et al, 2005; Bien-Ly et al, 2012; Liao et al, 2014; Lane-Donovan et al, 2016; Zheng et al, 2017)
Summary
Apolipoprotein E (APOE) in the central nervous system (CNS) has been the focus of study for two reasons: it is the most abundantly expressed apolipoprotein in the CNS (Bjorkhem & Meaney, 2004; Huang & Mahley, 2014), and inheritance of the E4 allele of the APOE gene profoundly impacts the risk for Alzheimer’s disease (AD), exacerbating amyloid deposition and worsening cognition and synapse loss. Sought to examine the effect of APOE depletion on neuronal function and synaptic integrity in adult or aged mice in both physiological and pathophysiological contexts. Neurons rely on cholesterol from glial cells for many processes; APOE plays an important role in modulating synapse growth, stabilization, and renewal in a physiological context (Holtzman & Fagan, 1998; Mauch et al, 2001). APOE is involved in removing cholesterol and lipids from the CNS, controlling the clearance of cellular debris and promoting remyelination in the aged CNS and some neurodegenerative diseases (Mahley, 1988; Zlokovic, 2011; Cantuti-Castelvetri et al, 2018). Other functions of APOE in the neural tissue include buffering oxidative stress (Evola et al, 2010; Chen et al, 2015) and preserving the integrity of the blood–brain barrier (Fullerton et al, 2001; HafeziMoghadam et al, 2007; Nishitsuji et al, 2011), further emphasizing the pivotal role of APOE in maintaining brain homeostasis
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