Elsevier

Progress in Neurobiology

Volume 194, November 2020, 101801
Progress in Neurobiology

Review article
Presynaptic failure in Alzheimer's disease

https://doi.org/10.1016/j.pneurobio.2020.101801Get rights and content

Highlights

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    Accumulating preclinical evidence suggests that key molecules implicated in the physiopathology of Alzheimer's disease (AD) exert a wide array of presynaptic functions.

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    Among this variety of mechanisms, three main mechanisms are highlighted.

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    APP fragments regulate synaptic transmission by binding to presynaptic receptors (e.g. nAChRs and GABAB receptors).

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    Presenilins control Ca2+ homeostasis and Ca2+ sensors involved in presynaptic plasticity.

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    Tau regulates the localization and mobility of presynaptic molecules and organelles, including mitochondria and synaptic vesicles.

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    Studies in human tissues from AD patients support the notion that pathological mechanisms in AD involve a strong presynaptic component.

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    Presynaptic failure in AD could be the ground for new therapeutical strategies targeting presynaptic receptors and mechanisms.

Abstract

Synaptic loss is the best correlate of cognitive deficits in Alzheimer’s disease (AD). Extensive experimental evidence also indicates alterations of synaptic properties at the early stages of disease progression, before synapse loss and neuronal degeneration. A majority of studies in mouse models of AD have focused on post-synaptic mechanisms, including impairment of long-term plasticity, spine structure and glutamate receptor-mediated transmission. Here we review the literature indicating that the synaptic pathology in AD includes a strong presynaptic component. We describe the evidence indicating presynaptic physiological functions of the major molecular players in AD. These include the amyloid precursor protein (APP) and the two presenilin (PS) paralogs PS1 or PS2, genetically linked to the early-onset form of AD, in addition to tau which accumulates in a pathological form in the AD brain. Three main mechanisms participating in presynaptic functions are highlighted. APP fragments bind to presynaptic receptors (e.g. nAChRs and GABAB receptors), presenilins control Ca2+ homeostasis and Ca2+-sensors, and tau regulates the localization of presynaptic molecules and synaptic vesicles. We then discuss how impairment of these presynaptic physiological functions can explain or forecast the hallmarks of synaptic impairment and associated dysfunction of neuronal circuits in AD. Beyond the physiological roles of the AD-related proteins, studies in AD brains also support preferential presynaptic alteration. This review features presynaptic failure as a strong component of pathological mechanisms in AD.

Introduction

Alzheimer's disease (AD), a neurodegenerative disorder that afflicts over 35 million people throughout the world, is characterized by memory loss and progressive cognitive decline. The characteristic neuropathological hallmarks of AD include amyloid plaques composed of extracellular deposits of Aβ peptides, and neurofibrillary tangles formed by hyper-phosphorylated tau, which progressively worsen over the course of the disease. Most AD cases are sporadic and of unknown etiology; however, in rare familial forms of AD (1-5% of the cases), mutations identified in the genes for the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) are causal to the disease. Because there is currently no treatment to prevent or reverse the disease, it is essential to continue exploring the diverse possible causes of AD. Among these causes, clinical and neuropathological studies have indicated that synaptic loss correlates strongly with the cognitive deficits seen in AD (DeKosky and Scheff, 1990; Scheff et al., 2007; Selkoe, 2002; Terry et al., 1991).

The implication of synaptic loss or synaptic dysfunction in the etiology of AD has been the subject of intense investigation, mainly using animal models of the disease (Forner et al., 2017; Marchetti and Marie, 2011). Notably, studies exploring the relationship between Aβ peptides, tau, and synaptic deficits and/or loss, have established molecular and physiological mechanisms relevant for memory and cognitive decline characteristic of AD. In addition, both Aβ and tau likely have physiological roles at the synapse. How Aβ oligomers affect synaptic transmission and post-synaptic plasticity (long-term potentiation and long-term depression) has been the subject of recent debates (see (Forner et al., 2017; Spires-Jones and Hyman, 2014)). In physiological conditions, tau is mainly an axonal protein which regulates microtubule stability and thus axonal transport. In AD, tau is hyper-phosphorylated and deposited in intracellular tangles, and pathological tau may lead to synaptic dysfunction by impairing cellular transport of important synaptic molecules at pre- and postsynaptic sides (Ittner and Ittner, 2018).

Altogether, our knowledge of the implication of Aβ peptides and tau in synaptic dysfunction, and the link between these two elements has increased significantly over the past years (Ittner and Ittner, 2018; Marchetti and Marie, 2011; Spires-Jones and Hyman, 2014), but many major questions remain. A majority of the studies have dealt with postsynaptic receptors and dendritic mechanisms, as well as postsynaptic forms of synaptic plasticity. There is however increasing evidence that AD is accompanied with deficits in presynaptic mechanisms and presynaptic forms of plasticity. Impairment of presynaptic mechanisms is expected to greatly influence the activity of neural circuits and can potentially participate in network hyperactivity as observed in mouse models of AD (Busche et al., 2008; Verret et al., 2012) and in AD patients (Bakker et al., 2012; Vossel et al., 2017), in particular by disrupting the excitatory/inhibitory synaptic balance (Wang et al., 2017). Although limited as compared to the post-synaptic counterpart, experimental evidence indicates that specifically interfering with presynaptic plasticity in vivo, influences memory processes (Monday et al., 2018). For instance, impairment of presynaptic long-term potentiation (LTP) at hippocampal mossy fiber synapses by genetic deletion (e.g in PACAP1, Rim1α, RAB3A, AKAP7 knock-out mice), correlates with memory deficits (Otto et al., 2001; Powell et al., 2004; Ruediger et al., 2011).

Here we will first present studies exploring the physiological function of proteins associated with AD, including APP (and APLPs), BACE1, ADAM10 and presenilin which participate in APP processing, the enzymatic cleavage products of APP, and finally the microtubule associated protein tau. We will also review a series of recent findings which demonstrate that synaptic dysfunction in AD pathology comprises a strong presynaptic component.

Section snippets

Abundance of APP and APP cleavage machinery in presynaptic terminals and synaptic vesicles

APP and the two paralogs APP-like proteins APLP1 and APLP2, are abundant proteins of the endoplasmic reticulum (ER) and trans-Golgi network (TGN) of neurons (Haass et al., 2012), hence highly expressed at the level of neuronal somata. In addition, the three paralogs are present at the synaptic level (see summary of their locations in Table 1). The synaptic localization of APLP1 is quite specific to the post-synaptic density (PSD), in rat, hamster and human (Kim et al., 1995). APP and APLP2 can

Tau in relation to synaptic dysfunction

Neurofibrillary tangles (NFTs), which constitute one of the neuropathological hallmark of AD, are composed of intracellular filamentous aggregates of hyperphosphorylated tau (Grundke-Iqbal et al., 1986). In physiological conditions, tau, a microtubule-binding protein (Fig. 3), is primarily an axonal protein that regulates microtubule stability and axonal transport (Wang and Mandelkow, 2015). It has been reported that synaptic dysfunction and abnormalities in axonal transport precede the

Presynaptic failure in AD, evidence from human studies

What is the evidence, beyond animal studies, for the contribution of a presynaptic failure component in AD pathology? Post-mortem studies have shown that alteration of synaptic markers (Terry et al., 1991) (Hamos et al., 1989) and synaptic loss (DeKosky and Scheff, 1990) correlate strongly with the cognitive deficits seen in AD (Selkoe, 2002). Synaptic pathology in AD represents a spectrum of alterations and pathogenic molecular cascades, spanning from minor functional alterations to

Conclusions

Here we review accumulating evidence suggesting that key molecules implicated in the physiopathology of AD exert a wide array of presynaptic functions (Table 1). Among this variety of mechanisms, three main mechanisms can be highlighted. Firstly, APP fragments regulate synaptic transmission by binding to presynaptic receptors (e.g. nAChRs and GABAB receptors). Secondly, presenilins control Ca2+ homeostasis and Ca2+ sensors involved in presynaptic plasticity. Thirdly, tau regulates the

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