c-Jun N-Terminal Kinases in Alzheimer’s Disease: A Possible Target for the Modulation of the Earliest Alterations

Abstract

Given the highly multifactorial origin of Alzheimer’s disease (AD) neuropathology, disentangling and orderly knowing mechanisms involved in sporadic onset are arduous. Nevertheless, when the elements involved are dissected into smaller pieces, the task becomes more accessible. This review aimed to describe the link between c-Jun N-terminal Kinases (JNKs), master regulators of many cellular functions, and the early alterations of AD: synaptic loss and dysregulation of neuronal transport. Both processes have a role in the posterior cognitive decline observed in AD. The manuscript focuses on the molecular mechanisms of glutamatergic, GABA, and cholinergic synapses altered by the presence of amyloid-β aggregates and hyperphosphorylated tau, as well as on several consequences of the disruption of cellular processes linked to neuronal transport that is controlled by the JNK-JIP (c-jun NH₂-terminal kinase (JNK)–interacting proteins (JIPs) complex, including the transport of AβPP or autophagosomes.

Keywords

Alzheimer’s disease amyloid-β axonal transport hyperphosphorylated tau JNK synapse loss

INTRODUCTION

The study of neurodegenerative diseases has evolved significantly in the last few decades and over time, increasing amounts of evidence are being gathered to understand the mechanisms involved in their appearance. Nevertheless, for now, the enigma of the onset of many of them and which effective therapies may stop their progress, remains unanswered.

One of the most prominent neurodegenerative pathologies is Alzheimer’s disease (AD) [1,2, 1,2]. Initial descriptions of AD established that it was characterized by cognitive affectations caused by neuronal loss [3]. It was also linked to the presence of amyloid-β (Aβ) depositions and hyperphosphorylated tau protein, which resulted in senile plaques and neurofibrillary tangles [3]. Nowadays, although it is still believed that they have a significant relevant function in the pathology, these classical hallmarks are not considered the cause of AD but rather one of its many features [4]. Other alterations include the appearance of metabolic imbalances [5 –7] and inflammatory stages’ development, which favor neurodegeneration [8 –10]. Several additional metabolic alterations have also been identified in AD pathology, including the appearance of oxidative stress [11, 12], dysregulation of autophagic activity [13, 14], and insulin resistance [15 –17], among others. Importantly, all these clinical alterations appear late in the time course of the disease, with the initial onset up to 20 years before the first clinical symptoms [18]. Consequently, new studies need to be run to analyze different potential elements that may be part of the pathology’s early stages. These would presumably identify additional targets involved in the development of effective treatments or preventive strategies.

Considering all these clinical manifestations, it is believed that AD could be a consequence of small changes in cellular functions that build up over time and eventually lead to the loss of synaptic contacts and the disruption of regular axonal transport [19 –22], which would lead to the clinical cognitive deficit that is observed in diagnosed AD patients. Considering the wide arrange of elements that seem to take part in the pathology, some research has focused on identifying factors that may behave as cellular master modulators.

The c-Jun N-terminal Kinases (JNK) are a subfamily of the mitogen-activated protein kinases responsible for several intra- and extracellular stimuli [23]. They are subdivided into three different isoforms (JNK1, JNK2, and JNK3), which are expressed from three different genes (Mapk8, Mapk9, and Mapk10) [24 –26]. Through their activity, they control a wide arrange of cellular mechanisms and, consequently, they are linked to both physiological and pathological situations [23]. Importantly, JNK regulation of many functions is precisely regulated, both in isoform and tissue manner [23]. Furthermore, gathered data has demonstrated that small and short-lasting changes in JNK activity are enough to regulate cellular responses and the maintenance of homeostatic patterns. Also, it has been described that an increase of JNK activity, either sustained or as acute bursts, leads to the activation of apoptotic mechanisms that occur in pathological stages [27, 28].

Given the significant involvement of the JNKs in many pathological stages, their role in the development of AD has also been studied in the past [28]. It has been described that there is increased activation of the JNKs in AD patient samples both from nervous tissue and cerebrospinal fluid [29]. JNK favors the amyloidogenic pathway of the amyloid-β protein precursor (AβPP) [30 –32]. Moreover, JNK directly phosphorylates of tau, a relatively early marker of AD [33]. Moreover, JNK activation has also been linked to the appearance of insulin resistance [34 –36], increasing sensibility of neurons to the activation of apoptotic pathways [37, 38]. Furthermore, the evidence shows a correlation between the JNK activation rate and cognitive affectation [29]. In addition, the JNK pathway also regulates microtubule and actin dynamics through the control of cytoskeletal proteins, a crucial process for correct axonal transport and the structure of presynaptic and postsynaptic domains [39, 40] (Fig. 1).

Fig. 1

c-Jun N-terminal Kinases (JNK) have been identified as target molecules for Alzheimer’s disease (AD) treatment. In the upper part of the figure, the AD pathology has been subdivided into different molecular stages. At the asymptomatic stage, the genetic factors are important for the beginning and the severity of the disease. During the early onset stage, Aβ aggregates and hyperphosphorylated tau induce synaptic loss and alteration in neuronal transport. These impairments trigger cell death and memory deficits that are observed in the symptomatic stage. In the lower part of the figure is shown the role of c-Jun N-terminal Kinases (JNK) in the different cellular processes that are affected along the AD stages, such as the tau phosphorylation, synaptic maintenance, neuronal transport, and cell viability.

Considering this information, some research gro-ups have already aimed to regulate JNK activity to prevent, revert, or ameliorate some of AD’s pathological features [28, 41]. This review will analyze the link between the JNKs and AD, specifically on the processes of synapse loss and the disruption of neuronal transport (Fig. 1).

SYNAPTIC LOSS AND JNKs

One of the earliest alterations of AD is the loss of synapses in most brain areas, an event that can be linked to the toxicity of Aβ, the hyperphosphorylation of tau, or other molecular dysregulations [42 –44]. The characterization of cerebrospinal fluid in cohort studies in patients of AD demonstrated an increase in the levels of circulating synaptic proteins, suggesting the disassembling of synaptic structures in the early non-symptomatic stages [45]. Animals models have corroborated these observations by reporting how synthesis of synaptic proteins is dysregulated [46].

The chronology of synaptic dysfunction in AD is not fully described, but some general hypotheses have been formulated. It is known that early events in AD and other dementias are triggered initially by the accumulation of Aβ oligomers in synaptic terminals, followed by axonal alterations, aberrant sprouting, and deficit of trophic factors [47]. Tau pathology is believed to appear secondarily or as a consequence of damage by oligomeric species of Aβ; late changes involve the loss of synaptic contacts, oxidative stress, inflammation, and neuronal loss [47]. Different studies have associated these molecular alterations with the activity of the JNKs [48, 28].

Glutamatergic synapses

Glutamatergic transmission is especially vulnerable to Aβ toxicity, producing a disruption of excitatory synaptic transmission and neuronal plasticity. Overstimulation of postsynaptic N-methyl-D-aspartate receptors (NMDAR) produces an increase in the levels of Aβ in the extrasynaptic space and hyperexcitability of neurons [49]. This neuronal hyperexcitability has been linked to the epileptic seizures observed in AD patients [50] (Fig. 2A). Moreover, it induces NMDAR internalization and posterior downregulation of extracellular signal-regulated kinase 1/2 (ERK1/2) that alters the synaptic plasticity [51 –53].

Fig. 2

Molecular mechanisms in glutamatergic synapses. One of the earliest alterations of AD is the loss of synapses linked to Aβ and hyperphosphorylated tau’s toxicity. Neuronal hyperexcitability. A) Accumulation of Aβ produces an increase in glutamate levels in the extrasynaptic space, which leads to an overstimulation of postsynaptic NMDAR and the hyperexcitability of neurons. JNKs can regulate calcium influx and synaptic plasticity. Moreover, the presence of hyperphosphorylated tau in synaptic areas alters their structure and neuronal transmission. Also, in astrocytes, Aβ interacts with glutamate transporters and inhibits glutamate clearance from the extrasynaptic space. B) In AD context, AMPAR in the postsynaptic regions has been observed to decrease their density, which induces synaptic depression and reduces synaptic plasticity. The AMPAR density is controlled by JNK signaling. Synaptic structure. D) Aβ species change the localization and expression of synaptic adhesion molecules and alter the actin cytoskeleton, producing a disruption of the cell structure and neuronal network impairments.

In astrocytes, Aβ interacts with glutamate transporters and inhibits glutamate clearance from the extrasynaptic space [54, 55]. Over time, this situation causes a drop in the expression of GluN2A and GluN2B subunits of NMDAR and GluA1 and GluA2 subunits of the α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR). Moreover, the density of AMPAR decreases in postsynaptic regions due to the effects of Aβ [56 –58]. This reduction induces synaptic depression and downregulates synaptic plasticity [59 –61]. Some studies report that the JNKs directly regulate the trafficking of AMPAR, controlling neuronal activity and plasticity [62, 63] (Fig. 2B).

The molecular mechanics that downgrade synaptic function and spines due to JNK activity are still under study but, several targets of JNK are cytosolic substrates that regulate cytoskeletal maintenance in dendrite and axon. In this line, the JNKs, specifically isoforms JNK2 and JNK3 are localized in presynaptic sites and interact with Syntaxin-1, Syntaxin-2, and Synaptosomal-Associated Protein, 25kDa (Snap25), suggesting that JNK activation in presynaptic regions might be related to glutamate neurotransmitter release in the synaptic space [64, 65]. JNK is activated in the postsynaptic space by a wide range of stimuli, including the excitotoxicity produced by NMDA receptors’ overactivation. In AD, JNK inhibition prevents neuronal death in cortical and hippocampal neurons, preventing caspase-3 activation [66] and the loss of glutamatergic synapses [67]. In this line, several studies have evidenced the neuroprotective effect of JNK inhibition in models of epilepsy [51 –53] (Fig. 2A).

Finally, Coffey and colleagues described in a recent publication that NMDA-mediated or corticosterone-induced cellular stress in hippocampal neurons in rats exerts rapid reorganization of actin dendritic spine structures through the activity of the JNKs. Furthermore, they supported these results with optogenetic control of the activity of the JNKs, which prevented the alteration of dendritic structures [68].

Cholinergic synapses

Loss of synapsis in basal forebrain cholinergic neurons (BFCNs) is linked to a deficit in stimulation and is involved in cognitive decline and memory loss in AD. In physiological conditions, BFCNs are continuedly maintained by neurotrophic signaling mediators like the brain-derived neurotrophic factor (BDNF) and the nerve growth factor (NGF), promoting cell survival, axon and dendrite maintenance. In AD patients, there is a deficit of these neurotrophic signals causing axonal pruning and degeneration, together with the activation of apoptotic pathways, mediated by the JNKs [69 –72] (Fig. 3).

Fig. 3

Cholinergic synapses. A) In basal forebrain cholinergic neurons, brain-derived neurotrophic factor (BDNF) and the nerve growth factor (NGF) promote cell survival and axon and dendrite maintenance. B) In AD, these processes have a dysregulation and occur an axonal pruning and degeneration. Change in neurotrophic levels reduced the Trk activation that enhances the apoptosis via JNK pathway.

Furthermore, increased expression of p75 in AD brains also favors neurotrophic signaling dysfunction [73, 74]. This mechanism has also been linked with an increase in the amyloidogenic pathway activity since p75 can interact with the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), an essential enzyme in the production of Aβ. This step in the formation of Aβ from AβPP has also been linked to the activity of the JNKs [75].

GABAergic synapses

Recent studies in AD patients and mouse models detected decrease expression on gamma-Amino-butyric acid (GABA) subunits receptor, indicating deficiencies in the inhibitory synaptic activity and neuronal transmission in the brain [76 –79]. Changes in the inhibitory transmission enhance neuronal hy-perexcitability, producing the epileptic seizures observed in AD [80]. Moreover, GABAergic impairment has been associated with depressive behavior in AD patients. Different studies in AD mouse models have indicated that abnormal levels of Aβ oligomers, an increase in tau hyperphosphorylation and aggregation interfere with GABA inhibitory activity (Fig. 4). This aberrant brain activity in the hippocampal and septohippocampal circuits has been correlated with cognitive impairment detected in AD mice models [81 –84].

Fig. 4

GABAergic transmission. GABA is the main inhibitory neurotransmission in the brain and crucial for learning tasks. In AD patients, significantly lower GABA neurotransmitter levels were observed, indicating synaptic function and neuronal transmission deficiency in AD. The changes in the inhibitory transmission enhance the neuronal hyperexcitability, which produces the epileptic seizures and apoptosis. JNK may regulate these processes.

As in the previously described alterations, the JNKs also seem to have a relationship with GABA neurotransmission. In several pathological environments, it has been described how GABA activity inhibits JNKs, providing neuroprotective profiles by reducing the activation of inflammatory and apoptotic responses [85 –88].

Tau hyperphosphorylation

The presence of hyperphosphorylated tau in synaptic structures alters their physiological conditions affects the localization of receptors and the distribution of postsynaptic density proteins needed for normal synaptic plasticity. Furthermore, species of hyperphosphorylated tau cause changes in synaptic structure and transmission. It has been observed that tau recruits Fyn to NMDAR/PSD95 complexes and is required to mediate excitotoxicity induced by Aβ and excessive glutamate levels (Fig. 2A) [89, 90]. Also, tau limits the binding of Synaptic Ras GTPase-activating protein 1 (SynGAP1) at postsynaptic regions, promoting local negative regulation of the excitotoxic ERK1/2 pathway [91 –93]. Furthermore, several studies have described that tau hyperphosphorylation is linked to JNK activity [33]. In fact, a recent study by He B and colleagues describes how downregulation of the activity of the JNKs reduced tau hyperphosphorylation rates [94].

Aβ accumulation

Besides modulating synaptic NMDA and AMPA receptors’ activity, Aβ species change the localization and expression of synaptic adhesion molecules, producing a disruption of the neuronal network (Fig. 2B). These proteins, such as Neural cell adhesion molecule 2 (NCAM2) and N-cadherin, are crucial for forming and maintaining synapses. Significantly, N-cadherin disruption by Aβ induces JNK activation in mice neuronal culture [95 –100].

Aβ species also disrupt the actin cytoskeleton, producing impairments in the structure of dendritic spines and altering neuronal transmission [101 –103] (Fig. 2B). Moreover, another study shows that Aβ activates the Rho-associated protein kinase (ROCK) pathway, which results in phosphorylation of cofilin-1, which changes actin dynamics [104].

Other cellular mechanisms controlled by JNKs, such as energetic imbalances, mitochondrial and en-doplasmic reticulum stress, or inflammatory res-ponses are potentially involved in synaptic loss [16 , 105–109].

ALTERATIONS IN NEURONAL TRANSPORT AND JNKS

JNK-interacting proteins (JIPs) control axonal transport

JIPs are scaffold proteins that recruit JNKs family members through JNK-binding domain (JBD) [110] and MAPK phosphatases through another subdomain [111]. These scaffolding proteins, depend on the stimuli, are specifically modulated and differentially located in the cell [112, 113]. JIPs are subdivided under four different members: JIP1/Islet-Brain 1 (IB), JIP2/Islet-Brain 2 (IB2), JIP3/stress-activated protein kinase-associated protein 1(JSAP) and JIP4/JNK-Associated Leucine-Zipper Protein (JLP). JIP1 and JIP3 are adaptors of molecular protein motors and regulators of synaptic vesicle movement and axonal growth [114, 115]. JIP3 regulates the transportation of phosphorylated AβPP in Threonine 668 by JNK in neurites. The deficit of JIP3 causes accumulation of phospho-AβPP in the soma that leads to neurotoxic effects [116, 117].

JIP and JNK control the autophagosomes movement

In neurons, autophagosome biogenesis may happen in distal axons and exhibit bidirectional movement (Fig. 5A) [118]. Sustained retrograde movement is needed to transit from the distal axon to the proximal axon or soma to fuse with lysosomes. Thus, the bidirectional movement of autophagic vacuole occurs and is regulated by a putative JNK activity that may impede the early exit of the autophagosomes. Phosphorylation of S421 of JIP1 by JNK may switch the direction of autophagosomes [119, 120]. Misfunction of the autophagy pathway has been related to AD since failures in this cellular process may contribute to a reduction in the clearance of Aβ aggregation (Fig. 5B) [118]. Therefore, JNK could be a target in the control of the autophagosomes movement.

Fig. 5

Neuronal transport alterations. A) In physiological conditions, a: APP is transported in synaptic vesicles that contain TrkA, GABAB receptors, BACE1 and PSEN1 (SV-APP vesicles). Vesicles are transported by kinesin-1 and scaffold protein JIP1/3, through microtubule roads in anterograde directions. b: The autophagic process degrades AβPP as it occurs with aged-organelles, misfolded protein and other intracellular material. Endosomes and autophagosomes are transported retrogradely by the cytoplasmic dynein motor protein. B) In pathological conditions, c: JIP1/3 phosphorylation by JNK is necessary to control the anterograde direction; dysfunction in the axonal transport leads to disassembling synaptic vesicle prompts the amyloidogenic pathway. d: Dysfunction of retrograde transport of lysosomes and autophagosome leads to axonal swelling and sustained activation of JNK3. This sustained activity might induce the amyloidogenic pathway and favor tau pathology.

Edwards and colleagues described a relevant role for JIP3 and JNK in the control of axonal transport. They found that in motor neurons of C. Elegans, UNC-16 (ortholog of JIP3) regulates the organelle entrance at the axon initial segment, controlling axon organelle composition. Thus, unc-16 null mutants accumulate high levels of organelles in their axons. Moreover, these mutants exhibit alterations in organelles’ bidirectional transport, mainly in lysosomes located in synaptic regions. The jnk1 C. Elegans null mutants also accumulate lysosomes in axons in lesser extension, supporting that UNC-16 and JNK-1 act as a part of the same process and regulate lysosomal transport [121].

The relevance of JIP3 in axonal transport was also reported in sensory axons of null mutant Jip3 zebrafish larvae. In this model, phospho-JNK3 tended to accumulate in axonal swellings with lysosomes. Other retrograde cargoes, such as autophagosomes or late endosomes, were not affected by lacking Jip3 [122]. Moreover, transportation of lysosomes and JNK3 seems to be independent because transfection of partial full Jip3 (lacking JBD) only restored lysosome accumulation but not the swelling and accumulation of phospho-JNK3 [122].

JNK3 induces accumulation of phospho-AβPP products in neuronal soma

AβPP protein is best known as the precursor of Aβ molecules. However, it is an integral membrane protein that can be found in presynaptic and postsynaptic areas where it forms trans-synaptic contacts that, in physiological conditions, contribute to the maintenance and stability of synaptic structures [123]. Proteomic studies of the presynaptic active site revealed that AβPP is an important molecule forming a part of the scaffold machinery that stabilizes the docking and release of synaptic vesicles into the synaptic cleft [124, 125]. Furthermore, AβPP takes a role in trafficking and localization of GABA-B receptors (GBRs) in the presynaptic space [126, 127] (Fig. 5A).

After synthesis, AβPP sorts inside synaptic vesicles (SV-AβPP) to the trans-Golgi network from where they are transported to both dendrites and axons. A deficit in AβPP axonal transport has been suggested to be part of AD pathology’s early event. SV-AβPPs are co-transported jointly with other components such as BACE1, Presenilin-1 (PS1), Tropomyosin kinase receptor A (TrkA, Growth Associated Protein 43 (GAP43), Synapsin I (Fig. 5A) [123, 128]; and evidence points out that missorted or stagnated AβPP vesicles might promote the activation of the amyloidogenic pathway, favoring the production of Aβ aggregates [129].

Yoon et al. clarified the role of JNK3 and the endocytic pathway in the reduction levels of the full-length AβPP on the cell surface [130]. They observed that JNK3 is the responsible isoform of AβPP phosphorylation at the threonine 668 site, favoring the internalization of AβPP in endosomes leading to neurotoxic effects (Fig. 5B) [130]. This study shows that in 5×FAD mice (transgenic Alzheimer’s disease model mice carrying five mutations in APP and PSEN1), phospho-JNK was colocalized with phospho-AβPP (threonine 668 site) in neuritic process hinting that activated JNK3 induces AβPP phosphorylation. In addition, tau hyperphosphorylation was found in the dystrophic axon, suggesting that JNK3 activation is a common event and may one of the first signals in triggering the brain pathology (Fig. 5B).

In this way, the neurotrophic factor NGF impedes the AβPP phosphorylation by the JNKs through the interaction with Isoform C of the SH2-containing sequence adaptor (ShcC). This effect increases the non-amyloidogenic pathway activity and promotes the localization of AβPP in the Golgi apparatus and the membrane cell surface [131]. Above observation has been supported at pharmacological level using peptide (D-JNKI1) that inhibits JNK activity in the brain parenchyma. Thus, the AβPP phosphorylation in Threonine 688 is blocked, reducing the formation of Aβ species, CTFβ fragments and Aβ oligomers in favor of the non-amyloidogenic pathway that prevents the loss of synaptic function in hippocampal neurons [32]. Therefore, the inhibition of JNK3 would be a potential target to block the amyloidogenic pathway’s development.

CONCLUSIONS

After reviewing evidence, it can be concluded that JNKs have an essential role in controlling initial events that lead to AD’s development. Their activation alters synaptic activity and neuronal transportation of AβPP and vesicles from endosomal recycling pathways (lysosomes and autophagosomes). Consequently, JNK dysregulation leads to loss of synaptic contacts, cell death, and amyloidogenic pathway upregulation. The importance of the JNK3 isoform in all these cellular processes has been highlighted.

For all that, the specific inhibition of JNK isoforms in precise neuron subpopulations could be a candidate strategy to restore axonal transport and physiological synaptic activity by preventing the amyloidogenic pathway’s consequences other alterations. Accordingly, to understand the role of JNK isoform in neuronal transport, synapsis formation and maintenance would be a useful tool to design new therapeutic approaches for AD.

Footnotes

ACKNOWLEDGMENTS

The research group is partly supported by funds from the Spanish Ministerio de Economía y Competitividad (SAF2017-84283-R to AC), the Generalitat de Catalunya (2014SGR-525 to AC) (2017 SGR 625 to CA) and CIBERNED (Grant CB06/05/2004 to AC). Fellowship Grodman Academic International Specialization Stays 2018 B (University of Guadalajara, Foundation USA) to RDCT.

Authors’ disclosures available online ().

References

Lane

, Hardy

, Schott

(2018) Alzheimer’s disease. Eur J Neurol25, 59–70.

Weller

, Budson

(2018) Current understanding of Alzheimer’s disease diagnosis and treatment. F1000Res7, F1000 Faculty Rev-1161.

Alzheimer

(1907) Über eine eigenartige Erkrankung der Hirnrinde. Allg Z Psychiatr Psych Med64, 146–148.

Karran

, Mercken

, Strooper De

(2011) The amyloid cascade hypothesis for Alzheimer’s disease: An appraisal for the development of therapeutics. Nat Rev Drug Discov10, 698–712.

Zhu

, Perry

, Moreira

, Aliev

, Cash

, Hirai

, Smith

(2006) Mitochondrial abnormalities and oxidative imbalance in Alzheimer disease. J Alzheimers Dis9, 147–153.

Toledo

, Arnold

, Kastenmüller

, Chang

, Baillie

, Han

, Thambisetty

, Tenenbaum

, Suhre

, Thompson

, John-Williams

, MahmoudianDehkordi

, Rotroff

, Jack

, Motsinger-Reif

, Risacher

, Blach

, Lucas

, Massaro

, Louie

, Zhu

, Dallmann

, Klavins

, Koal

, Kim

, Nho

, Shen

, Casanova

, Varma

, Legido-Quigley

, Moseley

, Zhu

, Henrion

MYR

, van der Lee

, Harms

, Demirkan

, Hankemeier

, van Duijn

, Trojanowski

, Shaw

, Saykin

, Weiner

, Doraiswamy

, Kaddurah-Daouk

; Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium (2017) Metabolic network failures in Alzheimer’s disease: A biochemical road map. Alzheimers Dement13, 965–984.

Clarke

, Ribeiro

, Frozza

, De

Felice FG

, Lourenco

(2018) Metabolic dysfunction in Alzhei-mer’s disease: From basic neurobiology to clinical ap-proaches. J Alzheimers Dis64, S405–S426.

Forloni

, Balducci

(2018) Alzheimer’s disease, oligomers, and inflammation. J Alzheimers Dis62, 1261–1276.

Newcombe

, Camats-Perna

, Silva

, Valmas

, Huat

, Medeiros

(2018) Inflammation: The link between comorbidities, genetics, and Alzheimer’s disease. J Neuroinflammation15, 1–26.

10.

Bostancıklıoglu

(2019) An update on the interactions between Alzheimer’s disease, autophagy and inflammation. Gene705, 157–166.

11.

Swerdlow

(2018) Mitochondria and mitochondrial cascades in Alzheimer’s disease. J Alzheimers Dis62, 1403–1416.

12.

Albensi

(2019) Dysfunction of mitochondria: Implications for Alzheimer’s disease. Int Rev Neurobiol145, 13–27.

13.

Zare-shahabadi

, Masliah

, Johnson

GVW

, Rezaei

(2015) Autophagy in Alzheimer’s disease. Rev Neurosci26, 385–395.

14.

Zhang

, Chen

, Zhao

, Ponnusamy

, Liu

(2017) The role of ubiquitin proteasomal system and autophagy-lysosome pathway in Alzheimer’s disease. Rev Neurosci28, 861–868.

15.

Steen

, Terry

, Rivera

, Cannon

, Neely

, Tavares

, Xu

, Wands

, de la Monte

(2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease –is this type 3 diabetes? J Alzheimers Dis7, 63–80.

16.

Ettcheto

, Cano

, Busquets

, Manzine

, Sanchez-López

, Castro-Torres

, Beas-Zarate

, Verdaguer

, García

, Olloquequi

, Auladell

, Folch

, Camins

(2019) A metabolic perspective of late onset Alzheimer’s disease. Pharmacol Res145, 104255.

17.

Folch

, Olloquequi

, Ettcheto

, Busquets

, Sanchez-López

, Cano

, Espinosa-Jimenez

, García

, Beas-Zarate

, Casadesús

, Bulló

, Auladell

, Camins

(2019) The involvement of peripheral and brain insulin resistance in late onset Alzheimer’s dementia. Front Aging Neurosci11, 1–16.

18.

Ettcheto

, Busquets

, Espinosa-Jimenez

, Verdaguer

, Auladell

, Camins

(2020) A chronological review of potential disease-modifying therapeutic strategies for Alzheimer’s disease. Curr Pharm Des26, 1286–1299.

19.

Vicario-Orri

, Opazo

, Muñoz

(2015) The pathophysiology of axonal transport in Alzheimer’s disease. J Alzheimers Dis43, 1097–1113.

20.

Wang

, Tan

, Yu

(2015) Axonal transport defects in Alzheimer’s disease. Mol Neurobiol51, 1309–1321.

21.

Kamat

, Kalani

, Rai

, Swarnkar

, Tota

, Nath

, Tyagi

(2016) Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease: Understanding the therapeutics strategies. Mol Neurobiol53, 648–661.

22.

Combs

, Mueller

, Morfini

, Brady

, Kanaan

(2019) Tau and axonal transport misregulation in tauopathies. Adv Exp Med Biol1184, 81–95.

23.

Sabapathy

(2012) Role of the JNK pathway in human diseases. Prog Mol Biol Transl Sci106, 145–169.

24.

Cui

, Zhang

, Xu

(2007) JNK pathway: Diseases and therapeutic potential. Acta Pharmacol Sin28, 601–608.

25.

Antoniou

, Borsello

(2012) The JNK signalling transduction pathway in the brain. Front Biosci (Elite Ed)4, 2110–2120.

26.

Coffey

(2014) Nuclear and cytosolic JNK signalling in neurons. Nat Rev Neurosci15, 285–299.

27.

Green

, Llambi

(2015) Cell death signaling. Cold Spring Harb Perspect Biol7, 1–24.

28.

Yarza

, Vela

, Solas

, Ramirez

(2016) c-Jun N-terminal Kinase (JNK) signaling as a therapeutic target for Alzheimer’s disease. Front Pharmacol6, 321.

29.

Gourmaud

, Paquet

, Dumurgier

, Pace

, Bouras

, Gray

, Laplanche

, Meurs

, Mouton-Liger

, Hugon

(2015) Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: Links to cognitive decline. J Psychiatry Neurosci40, 151–161.

30.

Morishima

, Gotoh

, Zieg

, Barrett

, Takano

, Flavell

, Davis

, Shirasaki

, Greenberg

(2001) β-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of fas ligand. J Neurosci21, 7551–7560.

31.

Savage

, Lin

, Ciallella

, Flood

, Scott

(2002) Activation of c-Jun N-Terminal Kinase and p38 in an Alzheimer’s disease model is associated with amyloid deposition. J Neurosci22, 3376–3385.

32.

Colombo

, Bastone

, Ploia

, Sclip

, Salmona

, Forloni

, Borsello

(2009) JNK regulates APP cleavage and degradation in a model of Alzheimer’s disease. Neurobiol Dis33, 518–525.

33.

Lagalwar

, Guillozet-Bongaarts

, Berry

, Binder

(2006) Formation of phospho-SAPK/JNK granules in the hippocampus is an early event in Alzheimer disease. J Neuropathol Exp Neurol65, 455–464.

34.

Sabio

, Das

, Mora

, Zhang

, Jun

, Ko

, Barrett

, Kim

, Davis

(2008) A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science322, 1539–1543.

35.

Giuliani

, Ottani

, Zaffe

, Galantucci

, Strinati

, Lodi

, Guarini

(2013) Hydrogen sulfide slows down progression of experimental Alzheimer’s disease by targeting multiple pathophysiological mechanisms. Neurobiol Learn Mem104, 82–91.

36.

Solas

, Aisa

, Tordera

, Mugueta

, Ramírez

(2013) Stress contributes to the development of central insulin resistance during aging: Implications for Alzheimer’s disease. Biochim Biophys Acta1832, 2332–2339.

37.

Marques

, Keil

, Bonert

, Steiner

, Haass

, Müller

, Eckert

(2003) Neurotoxic mechanisms caused by the Alzheimer’s disease-linked Swedish amyloid precursor protein. Mutation oxidative stress, caspases, and the JNK pathway. J Biol Chem278, 28294–28302.

38.

Sahara

, Murayama

, Lee

, Park

, Lagalwar

, Binder

, Takashima

(2008) Active c-jun N-terminal kinase induces caspase cleavage of Tau and additional phosphorylation by GSK-3β is required for tau aggregation. Eur J Neurosci27, 2897–2906.

39.

Conde

, Caceres

(2009) Microtubule assembly, organization and dynamics in axons and dendrites. Nat Rev Neurosci10, 319–332.

40.

Hotulainen

, Hoogenraad

(2010) Actin in dendritic spines: Connecting dynamics to function. J Cell Biol189, 619–629.

41.

Mehan

, Meena

, Sharma

, Sankhla

(2011) JNK: A stress-activated protein kinase therapeutic strategies and involvement in Alzheimer’s and various neurodegenerative abnormalities. J Mol Neurosci43, 376–390.

42.

Briggs

, Chakroborty

, Stutzmann

(2017) Emerging pathways driving early synaptic pathology in Alzheimer’s disease. Biochem Biophys Res Commun483, 988–997.

43.

, Wei

, Liu

, Hu

, Xie ji

, Zhu

, Liu

(2018) Synaptic dysfunction in Alzheimer’s dsease: Aβ, tau, and epigenetic alterations. Mol Neurobiol55, 3021–3032.

44.

Scheff

, Price

(2003) Synaptic pathology in Alzheimer’s disease: A review of ultrastructural studies. Neurobiol Aging24, 1029–1046.

45.

Lleó

, Alcolea

, Martínez-Lage

, Scheltens

, Parnetti

, Poirier

, Simonsen

, Verbeek

, Rosa-Neto

, Slot

RER

, Tainta

, Izaguirre

, Reijs

BLR

, Farotti

, Tsolaki

, Vandenbergue

, Freund-Levi

, Verhey

FRJ

, Clarimón

, Fortea

, Frolich

, Santana

, Molinuevo

, Lehmann

, Visser

, Teunissen

, Zetterberg

, Blennow

(2019) Longitudinal cerebrospinal fluid biomarker trajectories along the Alzheimer’s disease continuum in the BIOMARKAPD study. Alzheimers Dement15, 742–753.

46.

Cefaliello

, Penna

, Barbato

, Di Ruberto

, Mollica

, Trinchese

, Cigliano

, Borsello

, Chun

, Giuditta

, Perrone-Capano

, Miniaci

, Crispino

(2020) Deregulated local protein synthesis in the brain synaptosomes of a mouse model for Alzheimer’s disease. Mol Neurobiol57, 1529–1541.

47.

Overk

, Masliah

(2014) Pathogenesis of synaptic degeneration in Alzheimer’s disease and Lewy body disease. Biochem Pharmacol88, 508–516.

48.

Sclip

, Tozzi

, Abaza

, Cardinetti

, Colombo

, Calabresi

, Salmona

, Welker

, Borsello

(2014) c-Jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo. Cell Death Dis5, e1019.

49.

Bordji

, Becerril-Ortega

, Buisson

(2011) Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease. Rev Neurosci22, 285–294.

50.

Amatniek

, Hauser

, DelCastillo-Castaneda

, Jacobs

, Marder

, Bell

, Albert

, Brandt

, Stern

(2006) Incidence and predictors of seizures in patients with Alzheimer’s disease. Epilepsia47, 867–872.

51.

Auladell

, De Lemos

, Verdaguer

, Ettcheto

, Busquets

, Lazarowski

, Beas-Zarate

, Olloquequi

, Folch

, Camins

(2017) Role of JNK isoforms in the kainic acid experimental model of epilepsy and neurodegeneration. Front Biosci (Landmark Ed)22, 795–814.

52.

Busquets

, Ettcheto

, Cano

, R. Manzine

, Sanchez-Lopez

, Espinosa-Jimenez

, Verdaguer

, DarioCastro-Torres

, Beas-Zarate

, X. Sureda

, Olloquequi

, Auladell

, Folch

, Camins

(2019) Role of c-Jun N-Terminal Kinases (JNKs) in epilepsy and metabolic cognitive impairment. Int J Mol Sci21, 255.

53.

Tai

, Warner

, Jones

, Jung

, Concepcion

, Skyrud

, Fender

, Liu

, Williams

, Neumaier

, D’Ambrosio

, Poolos

(2017) Antiepileptic action of c-Jun N-terminal kinase (JNK) inhibition in an animal model of temporal lobe epilepsy. Neuroscience349, 35–47.

54.

Scimemi

, Meabon

, Woltjer

, Sullivan

, Diamond

, Cook

(2013) Amyloid-β1-42 slows clearance of synaptically released glutamate by mislocalizing astrocytic GLT-1. Ann Intern Med158, 5312–5318.

55.

Zoltowska

, Maesako

, Meier

, Berezovska

(2018) Novel interaction between Alzheimer’s disease-related protein presenilin 1 and glutamate transporter 1. Sci Rep8, 8718.

56.

Guntupalli

, Widagdo

, Anggono

(2016) Amyloid-β-induced dysregulation of AMPA receptor trafficking. Neural Plast.2016, 3204519.

57.

Hettinger

, Lee

, Bu

, Holtzman

, Cirrito

(2018) AMPA-ergic regulation of amyloid-β levels in an Alzheimer’s disease mouse model. Mol Neurodegener13, 22.

58.

Zhang

, Yin

, Ji

, Cai

, Zhao

, Li

, Tan

, Guo

(2017) Endophilin2 interacts with GluA1 to mediate AMPA receptor endocytosis induced by oligomeric amyloid-β. Neural Plast2017, 8197085.

59.

Bissen

, Foss

, Acker-Palmer

(2019) AMPA receptors and their minions: Auxiliary proteins in AMPA receptor trafficking. Cell Mol Life Sci76, 2133–2169.

60.

Diering

, Huganir

(2018) The AMPA receptor code of synaptic plasticity. Neuron100, 314–329.

61.

, Cong

, Sun

, Meng

(2018) Aβ1-42 regulates astrocytes through JNK/AP-1 pathway. Eur Rev Med Pharmacol Sci22, 2015–2021.

62.

Thomas

, Lin

, Nuriya

, Huganir

(2008) Rapid and bi-directional regulation of AMPA receptor phosphorylation and trafficking by JNK. EMBO J27, 361–372.

63.

Zhu

, Pak

, Qin

, Mccormack

, Kim

, Baumgart

, Velamoor

, Auberson

, Osten

, Van Aelst

, Sheng

, Zhu

(2005) Rap2-JNK removes synaptic AMPA receptors during depotentiation. Neuron46, 905–916.

64.

Biggi

, Buccarello

, Sclip

, Lippiello

, Tonna

, Rumio

, Di Marino

, Miniaci

, Borsello

(2017) Evidence of presynaptic localization and function of the c-Jun N-Terminal Kinase. Neural Plast2017, 6468356.

65.

Nisticò

, Florenzano

, Mango

, Ferraina

, Grilli

, Di Prisco

, Nobili

, Saccucci

, D’Amelio

, Morbin

, Marchi

, Mercuri

, Davis

, Pittaluga

, Feligioni

(2015) Presynaptic c-Jun N-terminal Kinase 2 regulates NMDA receptor-dependent glutamate release. Sci Rep5, 9035.

66.

Sclip

, Antoniou

, Colombo

, Camici

, Pozzi

, Cardinetti

, Feligioni

, Veglianese

, Bahlmann

, Cervo

, Balducci

, Costa

, Tozzi

, Calabresi

, Forloni

, Borsello

(2011) c-Jun N-terminal kinase regulates soluble Aβ oligomers and cognitive impairment in AD mouse model. J Biol Chem286, 43871–43880.

67.

Sclip

, Arnaboldi

, Colombo

, Veglianese

, Colombo

, Messa

, Mancini

, Cimini

, Morelli

, Antoniou

, Welker

, Salmona

, Borsello

(2013) Soluble Aβ oligomer-induced synaptopathy: c-Jun N-terminal kinase’s role. J Mol Cell Biol5, 277–279.

68.

Hollos

, John

, Lehtonen

, Coffey

(2020) Optogenetic control of spine-head JNK reveals a role in dendritic spine regression. eNeuro7, ENEURO.0303-19.2019.

69.

Huang

, Duan

, Sun

, Wang

, Zhao

, Geng

, Yan

, Sun

, Chen

(2011) JIP3 mediates TrkB axonal anterograde transport and enhances BDNF signaling by directly bridging TrkB with kinesin-1. J Neurosci31, 10602–10614.

70.

Sun

, Li

, Ma

, Guo

, Jiang

, Hou

, Huang

, Chen

(2017) JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport by activating kinesin-1. Cell Mol Life Sci74, 4027–4044.

71.

Colacurcio

, Pensalfini

, Jiang

, Nixon

(2018) Dysfunction of autophagy and endosomal-lysosomal pathways: Roles in pathogenesis of Down syndrome and Alzheimer’s Disease. Free Radic Biol Med114, 40–51.

72.

Escudero

, Cabeza

, Moya-Alvarado

, Maloney

, Flores

, Wu

, Court

, Mobley

, Bronfman

(2019) c-Jun N-terminal kinase (JNK)-dependent internalization and Rab5-dependent endocytic sorting mediate long-distance retrograde neuronal death induced by axonal BDNF-p75 signaling. Sci Rep9, 6070.

73.

Sycheva

, Sustarich

, Zhang

, Selvaraju

, Geetha

, Gearing

, Babu

(2019) Pro-nerve growth factor induces activation of RhoA kinase and neuronal cell death. Brain Sci9, 204.

74.

Fahnestock

, Shekari

(2019) ProNGF and neurodegeneration in Alzheimer’s disease. Front Neurosci13, 129.

75.

Saadipour

, Mañucat-Tan

, Lim

, Keating

, Smith

, Zhong

, Liao

, Bobrovskaya

, Wang

Y-J

, Chao

, Zhou

X-F

(2018) p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis. J Neurochem144, 302–317.

76.

Palop

, Mucke

(2016) Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci17, 777–792.

77.

Nava-Mesa

, Jimenez-Díaz

, Yajeya

, Navarro-Lopez

(2014) GABAergic neurotransmission and new strategies of neuromodulation to compensate synaptic dysfunction in early stages of Alzheimer’s disease. Front Cell Neurosci8, 167.

78.

Verret

, Mann

, Hang

, Barth

AMI

, Cobos

, Ho

, Devidze

, Masliah

, Kreitzer

, Mody

, Mucke

, Palop

(2012) Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell149, 708–721.

79.

Govindpani

, Calvo-Flores Guzmán

, Vinnakota

, Waldvogel

, Faull

, Kwakowsky

(2017) Towards a better understanding of GABAergic remodeling in Alzheimer’s disease. Int J Mol Sci18, 1813.

80.

Selkoe

(2019) Early network dysfunction in Alzheimer’s disease. Science365, 540–541.

81.

Rubio

, Vega-Flores

, Martínez

, Bosch

, Perez-Mediavilla

, Ríodel

, Gruart

, Delgado-García

, Soriano

, Pascual

(2012) Accelerated aging of the GABAergic septohippocampal pathway and decreased hippocampal rhythms in a mouse model of Alzheimer’s disease. FASEB J26, 4458–4467.

82.

Soler

, Dorca-Arevalo

, Gonzalez

, Rubio

, Ávila

, Soriano

, Pascual

(2017) The GABAergic septohippocampal connection is impaired in a mouse model of tauopathy. Neurobiol Aging49, 40–51.

83.

Saiz-Sanchez

, Ubeda-Bañon

, De la Rosa-Prieto

, Martinez-Marcos

(2012) Differential expression of interneuron populations and correlation with amyloid-β deposition in the olfactory cortex of an AβPP/PS1 transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis31, 113–129.

84.

, Zhao

, Han

, Zhang

(2020) GABAergic inhibitory interneuron deficits in Alzheimer’s disease: Implications for treatment. Front Neurosci14, 660.

85.

, Li

, Yin

, Zhang

(2008) Additive neuroprotection of GABA A and GABA B receptor agonists in cerebral ischemic injury via PI-3K/Akt pathway inhibiting the ASK1-JNK cascade. Neuropharmacology54, 1029–1040.

86.

Wang

, Sui

, Liu

, Peng

, Liu

, Luo

, Fan

, Liu

, Lu

(2018) Protective roles of hepatic gamma-aminobutyric acid signaling in acute ethanol exposure-induced liver injury. J Appl Toxicol38, 341–350.

87.

, Shan

, Zheng

, Pei

(2014) β-arrestin promotes c-Jun N-terminal kinase mediated apoptosis via a GABABR·β-arrestin·JNK signaling module. Asian Pacific J Cancer Prev15, 1041–1046.

88.

Hall

, Hader

, Kondiles

(2019) The gamma-aminobutyric acid (GABA)A receptor modulates the cytokine response to rhinovirus exposure in human monocytic cells. FASEB J33, 792.4–792.4.

89.

Ittner

, Ittner

(2018) Dendritic tau in Alzheimer’s disease. Neuron99, 13–27.

90.

Ittner

, Ke

, Delerue

, Bi

, Gladbach

, van Eersel

, Wölfing

, Chieng

, Christie

, Napier

, Eckert

, Staufenbiel

, Hardeman

, Götz

(2010) Dendritic function of tau mediates amyloid-β toxicity in Alzheimer’s disease mouse models. Cell142, 387–397.

91.

Hoover

, Reed

, Su

, Penrod

, Kotilinek

, Grant

, Pitstick

, Carlson

, Lanier

, Yuan

L-L

, Ashe

, Liao

(2010) Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron68, 1067–1081.

92.

Crespo-Biel

, Theunis

, Van Leuven

(2012) Protein tau: Prime cause of synaptic and neuronal degeneration in Alzheimer’s disease. Int J Alzheimers Dis2012, 251426.

93.

Marin

, Ziburkus

, Jankowsky

, Rasband

(2016) Amyloid-β plaques disrupt initial axon segments. Exp Neurol281, 93–98.

94.

, Chen

, Zeng

, Tong

, Zheng

(2020) MicroRNA-326 decreases tau phosphorylation and neuron apoptosis through inhibition of the JNK signaling pathway by targeting VAV1 in Alzheimer’s disease. J Cell Physiol235, 480–493.

95.

Andreyeva

, Nieweg

, Horstmann

, Klapper

, Müller-Schiffmann

, Korth

, Gottmann

(2012) C-terminal fragment of N-cadherin accelerates synapse destabilization by amyloid-β. Brain135, 2140–2154.

96.

Asada-Utsugi

, Uemura

, Noda

, Kuzuya

, Maesako

, Ando

, Kubota

, Watanabe

, Takahashi

, Kihara

, Shimohama

, Takahashi

, Berezovska

, Kinoshita

(2011) N-cadherin enhances APP dimerization at the extracellular domain and modulates Aβ production. J Neurochem119, 354–363.

97.

Gnanapavan

, Giovannoni

(2013) Neural cell adhesion molecules in brain plasticity and disease. Mult Scler Relat Disord2, 13–20.

98.

Leshchyns’ka

, Sytnyk

(2016) Synaptic cell adhesion molecules in Alzheimer’s disease. Neural Plast2016, 6427537.

99.

Sytnyk

, Leshchyns’ka

, Schachner

(2017) Neural cell adhesion molecules of the immunoglobulin superfamily regulate synapse formation, maintenance, and function. Trends Neurosci40, 295–308.

100.

Wennström

, Nielsen

(2012) Cell adhesion molecules in Alzheimer’s disease. Degener Neurol Neuromuscul Dis2, 65–77.

101.

Bamburg

, Bernstein

(2016) Actin dynamics and cofilin-actin rods in Alzheimer disease. Cytoskeleton73, 477–497.

102.

Fulga

, Elson-Schwab

, Khurana

, Steinhilb

, Spires

, Hyman

, Feany

(2007) Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol9, 139–148.

103.

Kommaddi

, Das

, Karunakaran

, Nanguneri

, Bapat

, Ray

, Shaw

, Bennett

, Nair

, Ravindranath

(2018) Aβ mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer’s disease. J Neurosci38, 1085–1099.

104.

Rush

, Martinez-Hernandez

, Dollmeyer

, Frandemiche

, Borel

, Boisseau

, Jacquier-Sarlin

, Buisson

(2018) Synaptotoxicity in Alzheimer’s disease involved a dysregulation of actin cytoskeleton dynamics through cofilin 1 phosphorylation. J Neurosci38, 10349–10361.

105.

Nonaka

, Nakanishi

(2019) Microglial clearance of focal apoptotic synapses. Neurosci Lett707, 134317.

106.

Galloway

, Phillips

AEM

, Owen

DRJ

, Moore

(2019) Phagocytosis in the brain, Homeostasis and disease. Front Immunol10, 790.

107.

Weinhard

, Di Bartolomei

, Bolasco

, Machado

, Schieber

, Neniskyte

, Exiga

, Vadisiute

, Raggioli

, Schertel

, Schwab

, Gross

(2018) Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun9, 1–14.

108.

Colom-Cadena

, Spires-Jones

, Zetterberg

, Blennow

, Caggiano

, Dekosky

, Fillit

, Harrison

, Schneider

, Scheltens

, De Haan

, Grundman

, Van Dyck

, Izzo

, Catalano

(2020) The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease. Alzheimers Res Ther12, 1–12.

109.

Jackson

, Jambrina

, Li

, Marston

, Menzies

, Phillips

, Gilmour

(2019) Targeting the synapse in Alzheimer’s disease. Front Neurosci13, 735.

110.

Ito

, Yoshioka

, Akechi

, Yamashita

, Takamatsu

, Sugiyama

, Hibi

, Nakabeppu

, Shiba

, Yamamoto

K-I

(1999) JSAP1, a novel Jun N-terminal protein kinase (JNK)-binding protein that functions as a scaffold factor in the JNK signaling pathway. Mol Cell Biol19, 7539$#x2013;7548.

111.

Willoughby

, Perkins

, Collins

, Whitmarsh

(2003) The JNK-interacting protein-1 scaffold protein targets MAPK phosphatase-7 to dephosphorylate JNK. J Biol Chem278, 10731–10736.

112.

Koon

, Koh

, Chiam

(2014) Computational modeling reveals optimal strategy for kinase transport by microtubules to nerve terminals. PLoS One9, e92437.

113.

Kholodenko

(2002) MAP kinase cascade signaling and endocytic trafficking: A marriage of convenience? . Trends Cell Biol12, 173–177.

114.

Verhey

, Meyer

, Deehan

, Blenis

, Schnapp

, Rapoport

, Margolis

(2001) Cargo of kinesin identified as JIP scaffolding proteins and associated signaling molecules. J Cell Biol152, 959–970.

115.

Dajas-Bailador

, Jones

, Whitmarsh

(2008) The JIP1 scaffold protein regulates axonal development in cortical neurons. Curr Biol18, 221–226.

116.

Chang

, Kim

, Ha

, Shin

, Jeong

, Lee

, Park

, Kim

, Baik

, Suh

(2006) Phosphorylation of amyloid precursor protein (APP) at Thr668 regulates the nuclear translocation of the APP intracellular domain and induces neurodegeneration. Mol Cell Biol26, 4327–4338.

117.

Muresan

, Muresan

(2005) c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein. J Neurosci25, 3741–3751.

118.

Meng

, Lin

, Zhuang

, Huang

, He

, Hu

, Gong

, Feng

(2019) Recent progress in the role of autophagy in neurological diseases. Cell Stress3, 141–161.

119.

, Holzbaur

ELF

(2013) JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors. J Cell Biol202, 495–508.

120.

Fu meng

, Holzbaur

ELF

(2014) Integrated regulation of motor-driven organelle transport by scaffolding proteins. Trends Cell Biol24, 564–574.

121.

Edwards

, Yu

, Hoover

, Phillips

, Richmond

, Miller

(2013) An organelle gatekeeper function for Caenorhabditis elegans UNC-16 (JIP3) at the axon initial segment. Genetics194, 143–161.

122.

Drerup

, Nechiporuk

(2013) JNK-interacting protein 3 mediates the retrograde transport of activated c-Jun N-terminal kinase and lysosomes. PLoS Genet9, e1003303.

123.

Hoe

H-S

, Lee

H-K

, Pak

DTS

(2012) The upside of APP at synapses. CNS Neurosci Ther18, 47–56.

124.

Laßek

, Weingarten

, Wegner

, Mueller

, Rohmer

, Baeumlisberger

, Arrey

, Hick

, Ackermann

, Acker-Palmer

, Koch

, Müller

, Karas

, Volknandt

(2016) APP is a context-sensitive regulator of the hippocampal presynaptic active zone. PLoS Comput Biol12, e1004832.

125.

Südhof

(2012) The presynaptic active zone. Neuron75, 11–25.

126.

Dinamarca

, Raveh

, Schneider

, Fritzius

, Früh

, Rem

, Stawarski

, Lalanne

, Turecek

, Choo

, Besseyrias

, Bildl

, Bentrop

, Staufenbiel

, Gassmann

, Fakler

, Schwenk

, Bettler

(2019) Complex formation of APP with GABA_B receptors links axonal trafficking to amyloidogenic processing. Nat Commun10, 1331.

127.

Fritzius

, Bettler

(2020) The organizing principle of GABA(B) receptor complexes: Physiological and pharmacological implications. Basic Clin Pharmacol Toxicol126 Suppl, 25–34.

128.

Müller

, Kins

(2002) APP on the move. Trends Mol Med8, 152–155.

129.

Stokin

, Lillo

, Falzone

, Brusch

, Rockenstein

, Mount

, Raman

, Davies

, Masliah

, Williams

, Goldstein

LSB

(2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science307, 1282–1288.

130.

Yoon

, Park

, Ryu

, Ozer

, Tep

, Shin

, Lim

, Pastorino

, Kunwar

, Walton

, Nagahara

, Lu

, Nelson

, Tuszynski

, Huang

(2012) JNK3 perpetuates metabolic stress induced by Aβ peptides. Neuron75, 824–837.

131.

Triaca

, Sposato

, Bolasco

, Ciotti

, Pelicci

, Bruni

, Cupidi

, Maletta

, Feligioni

, Nisticò

, Canu

, Calissano

(2016) NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: Relevance for Alzheimer’s disease. Aging Cell15, 661–672.