Bidirectional relationships between sleep and amyloid-beta in the hippocampus

Highlights

• Hippocampal Aß pathology is linked to changes in wake/sleep duration.

• Hippocampal Aß pathology also associates with changes in wake/sleep quality.

• Sleep disturbances reciprocally impact Aß pathology in the hippocampus.

• Future research should assess mechanisms and specificity of these relationships.

Abstract

Alzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by progressive hippocampal-dependent explicit memory deficits that begin at the onset of the illness. An early hallmark of AD is the accumulation of amyloid-beta (Aß) proteins in brain structures involved in encoding and consolidation of memory, like the hippocampus and prefrontal cortex. Aß neurotoxicity is known to induce synaptic dysfunctions and neuronal death leading to cognitive decline. Another recurrent event observed in AD is sleep disturbances. Decreased sleep duration, sleep fragmentation, and circadian alterations are often observed in early AD. The origin of these disturbances, and especially the specific contribution of the hippocampal Aß pathology, remains to be determined. It is required to identify mechanisms impacting wakefulness and sleep architecture and microarchitecture given the role of sleep in memory encoding and consolidation. Sleep perturbations in AD are thus likely contributing to memory decline in the course of the disease. The central aim of this review is to address the bidirectional relationship between sleep and hippocampal Aß by discussing the literature featuring data on wakefulness and sleep variables (i.e., duration, electroencephalographic activity, daily distribution) in AD mouse models and on the effect of enforced sleep loss on Aß pathology in the hippocampus. The current state of knowledge on this topic emphasizes a clear need for more efforts to assess the precise impact of hippocampal Aß on wakefulness and sleep quality as well as the mechanisms mediating their reciprocal relationship.

Introduction

Alzheimer’s disease (AD) is the most common form of dementia among people over 65-years old, and affects around one in three individuals over 85-years (Ferri et al., 2005, Lautenschlager et al., 1996). The earliest clinical symptom of this age-related neurodegenerative disorder is decline in hippocampal-dependent explicit memory (memory for facts and events) (Braak and Braak, 1991, Lambon Ralph et al., 2003, Welsh et al., 1992). One of the most studied neuropathological hallmarks of AD is the accumulation of amyloid-beta (Aβ) proteins which begins approximately 10–15 years before clinical symptoms become apparent (Holtzman et al., 2011, Murphy and LeVine, 2010, Sadigh-Eteghad et al., 2015, Sperling et al., 2011). This protein origins from a cleavage of the amyloid precursor protein (APP) and tends to oligomerize rapidly into soluble amyloid-beta oligomers (Aßo) to eventually form insoluble fibrils and senile plaques (Findeis, 2007). Soluble Aβo were shown to be the most toxic form of the protein and to induce synaptic dysfunction, neuronal death, and cognitive deficits by molecular mechanisms that still need to be fully established (Brouillette, 2014, Ma and Klann, 2012).

Another hallmark that is being increasingly investigated in AD patients is disturbance in sleep and circadian rhythms. Cognitive decline in early AD was indeed shown to be accompanied by difficulty to induce and maintain sleep, shifts in sleep/wake pattern, reduction in rapid eye movement (REM) sleep, and circadian alterations (Peter-Derex et al., 2015, Petit et al., 2004). It seems particularly important to understand the origin of these sleep disturbances in AD given that there is a large body of evidence showing a marked influence of the different sleep stages on hippocampus-dependent memory processes. For example, slow wave oscillations observed during non-REM (NREM) sleep are crucial for memory consolidation after learning a spatial task (Diekelmann & Born, 2010). Furthermore, REM sleep, characterized by electroencephalographic (EEG) theta (4–9 Hz) activity, has been shown to have roles in spatial and contextual memory consolidation (Boyce, Glasgow, Williams, & Adamantidis, 2016). The hippocampus is also involved in the generation of sleep oscillations related to memory processes, such as NREM sleep sharp wave ripples and REM sleep theta activity (Nokia et al., 2012, Boyce et al., 2016).

In view of that, sleep deprivation (SD) in rodents and humans is known to have deleterious impacts on learning and memory consolidation. For instance, deprivation of REM sleep in mice has been shown to induce deficits in hippocampus-dependent memory consolidation (Chen, Tian, & Ke, 2014), without affecting hippocampus-independent memory (Rasch, Pommer, Diekelmann, & Born, 2009). Also, there is considerable evidence that the hippocampus is strongly affected by SD. In fact, SD impacts hippocampal volume, plasticity and memory processing leading to memory deficits (Kreutzmann et al., 2015, Havekes and Abel, 2017). The inter-dependency between hippocampal and sleep functions including the susceptibility of this brain region to sleep loss could exacerbate vulnerability to other disturbing factors, such as the accumulation of toxic Aßo in AD.

Two main topics will be addressed in this review. First, we will examine the growing body of evidence indicating that accumulation of Aß in the hippocampus has an impact on wakefulness/sleep duration, consolidation and fragmentation, electroencephalographic (EEG) activity, as well as daily distribution. The main evidences are based on studies using transgenic AD mouse models, in which the production and accumulation of Aß are modified in the hippocampus (Table 1 lists the main characteristics of five of these AD models), and from complementary human studies. Sleep features of animal models injected with Aβ directly in the hippocampus will also be reviewed, although it should be noted that literature using this type of model is less abundant than studies using transgenic mice. Second, we will review the literature focusing on how sleep disturbance or deprivation can reciprocally affect Aß pathology in the hippocampus.