The Role of Rab GTPases in Alzheimer's Disease - ACS Chemical

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The Role of Rab GTPases in Alzheimer’s Disease Xian Zhang, Timothy Y. Huang, Joel Yancey, Hong Luo, and Yunwu Zhang ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00387 • Publication Date (Web): 27 Sep 2018 Downloaded from http://pubs.acs.org on September 28, 2018

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ACS Chemical Neuroscience

The Role of Rab GTPases in Alzheimer’s Disease

Xian Zhang,† Timothy Y. Huang,‡ Joel Yancey,‡ Hong Luo,† and Yun-wu Zhang†,*

†

Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research,

Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian 361102, China ‡

Neuroscience Initiative, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla,

CA 92037, USA

*

Corresponding author: Yun-wu Zhang, Fujian Provincial Key Laboratory of

Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, Fujian 361102, China. E-mail: [email protected].

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ACS Chemical Neuroscience 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ABSTRACT: Alzheimer's disease (AD) comprises two major pathological hallmarks: extraneuronal deposition of β-amyloid (Aβ) peptides (“senile plaques”) and intraneuronal aggregation of the microtubule-associated protein tau (“neurofibrillary tangles”). Aβ is derived from sequential cleavage of the β-amyloid precursor protein by β- and γ-secretases, while aggregated tau is hyperphosphorylated in AD. Mounting evidence suggests that dysregulated trafficking of these AD-related proteins contributes to AD pathogenesis. Rab proteins are small GTPases that function as master regulators of vesicular transport and membrane trafficking. Multiple Rab GTPases have been implicated in AD-related protein trafficking and their expression has been observed to be altered in postmortem AD brain. Here we review current implicated roles of Rab GTPase dysregulation in AD pathogenesis. Further elucidation of the pathophysiological role of Rab GTPases will likely reveal novel targets for AD therapeutics.

KEYWORDS: β-amyloid, β-amyloid precursor protein, Alzheimer’s disease, Rab GTPases, tau, trafficking


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1. INTRODUCTION Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease described thus far, and is clinically characterized by progressive cognitive impairment and memory loss. Two classical pathological hallmarks in AD include the appearance of intraneuronal neurofibrillary tangles (NFTs) and extraneuronal senile plaques.1, 2 NFTs are pathological anomalies consisting of aberrant phosphorylated forms of the microtubule-associated protein tau, which is predominantly hyperphosphorylated by CDK5 and GSK-3 kinases in AD.1,

3

In contrast, senile plaques consist of a heterogeneous population of

proteolytically-generated β-amyloid (Aβ) peptides.4, 5 Results from mounting studies suggest that excessive Aβ in the brain, due either to elevated production or reduced clearance, initiates AD pathogenesis.6, 7 Aβ is derived from amyloidogenic processing of the β-amyloid precursor protein (APP), whereby APP is first cleaved by β-secretase within the ectodomain, generating a soluble sAPPβ fragment and a membrane-anchored β-carboxyl-terminal fragment (βCTF) fragment. The predominant β-secretase enzyme for APP cleavage is BACE1 (beta-site APP-cleaving enzyme 1), which is a type-I transmembrane aspartyl protease.8-11 After β-cleavage, APP βCTF can be cleaved by γ-secretase within the lipid bilayer, leading to the generation of Aβ and APP intracellular domain (AICD). γ-secretase is a high molecular weight complex consisting of at least four transmembrane components: Presenilin (PS1 or PS2), nicastrin, anterior pharynx-defective-1 (APH-1), and presenilin enhancer-2 (PEN2).12, 13 Apart from amyloidogenic processing, APP can also be cleaved by α-secretases within



the Aβ domain, releasing an sAPPα fragment. APP processing through this non-amyloidogenic pathway precludes Aβ production and has neurotrophic and neuroprotective effects.14,

15

Several members of the ADAM (a disintegrin and

metalloproteinase) family have been found to possess α-secretase activity, such as ADAM10, ADAM17 and ADAM9.15, 16 Interestingly, α-secretases cleave APP primarily at the cell surface, whereas β- and γ-secretases primarily cleave APP in acidified trans-Golgi and endosomal environments, thereby generating Aβ within the lumen of endosomes, leading to their eventual extracellular secretion.17 Therefore, APP trafficking and its coincident localization with related secretases in endosomes is crucial for Aβ production. This process requires the participation of various trafficking factors including the Rab (Ras-associated binding) family of GTPases; dysregulation of these trafficking factors may affect Aβ production and thus potentially contribute to AD pathogenesis.

2. RAB GTPASES Rab proteins are low molecular weight GTPases that belong to the Ras superfamily.18 By tethering/docking vesicles to their respective compartments, Rab GTPases function as molecular switches, alternating between GTP-bound active and GDP-bound inactive forms which can direct vesicle transport to their appropriate destinations.19 Cycling between GTP- and GDP-bound forms is tightly controlled by protein regulators such as GTPase activating proteins (GAPs), GDP dissociation inhibitors (GDIs) and Guanine exchange factors (GEFs): GAPs inactivate GTP-bound GTPases by promoting GTP


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hydrolysis to GDP; GDIs stabilize GDP-bound GTPases; and GEFs activate GTPases by facilitating the exchange of GDP to GTP.18 A single Rab GTPase may exert various trafficking-dependent functions in conjunction with its regulators;20 for example, the well characterized RAB5A/RAB5 protein has been found to interact with over 20 different effectors19 and to participate in endocytic vesicle formation, uncoating, movement,21-23 and endosome fusion.24 More than 60 human Rab GTPases have been identified.25 The overrepresentation of Rab GTPases, in addition to their functional complexity, highlight their importance in vesicle trafficking. Members of the evolutionarily conserved Rab GTPase protein family regulate fundamental vesicle transport pathways and are often ubiquitously expressed. Conversely, Rab family members with poor conservation are typically enriched in various tissues and function in more specific transport pathways.18,

20

For example,

RAB3A, RAB8A/RAB8 and RAB23 are highly expressed in the brain and participate in synaptic vesicle exocytosis, postsynaptic glutamate receptor dynamics, neurite growth, and/or neural development.26 Dysregulation of Rab GTPases may therefore contribute to the pathogenesis of some diseases. Indeed, enlargement of RAB5-positive early endosomes has been observed in AD patient brain, and these endosomal pathological features can be detected in brain regions lacking senile plaques or tau tangles.27, 28 This suggests that early endosomal abnormalities occur prior to the appearance of Aβ or tau pathology. Nevertheless, causal and consequential relationships underlying the association of AD with various Rab GTPases have yet to be determined. One recent



review classified the association relevance of Rab GTPases with neurodegenerative diseases into three categories: Rab GTPases whose mutations are the primary cause of neurodegeneration (Class A); Rab GTPases which do not trigger neurodegeneration, but rather affects pathology (Class B); and Rab GTPases which are neither the neurodegenerative triggers nor consequential components to pathology (Class C).29 Through this classification scheme, we similarly categorized Rab GTPases to clarify their respective causal and effectual relationship with AD (Table 1).

3. GENETIC ASSOCIATION OF RAB GTPASES WITH AD Genetic association often provides direct evidence for the causal role of a gene in disease. Mutations in genes encoding APP and the γ-secretase component Presenilin1/2 can enhance the production of total Aβ or the more toxic Aβ42 species and lead to familial, early onset AD (fAD or EOAD), providing strong genetic evidence in support of the “Aβ cascade hypothesis” in AD pathogenesis. However, familial mutations only account for a small minority of AD cases; over 95% of AD cases manifest sporadic, late onset (sAD or LOAD) variants of the disease which lack a well-characterized etiology. The ε4 allele of the APOE gene is the strongest genetic risk factor identified thus far for LOAD.30 Although cholesterol transport is thought to be the primary function of the APOE gene product, apolipoprotein E (apoE), apoE also regulates Aβ metabolism through cellular uptake and degradation.30 More recently, large‐scale genome‐wide association studies (GWAS) and meta‐analyses have identified more than 20 genes associated with


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LOAD.31-35 Interestingly, a significant number of the newly identified AD-linked genes encode proteins that play roles in endocytic trafficking, such as PICALM, BIN1, SORL1 and CD2AP.36 Mutations in genes encoding Rab GTPases have been associated with various diseases. For example, RAB27A/RAB27 mutations have been described in Griscelli syndrome, an autosomal recessive disease with defective melanosome transport and deregulated T lymphocyte and macrophage activation.37, 38 RAB23 mutations have been linked to Carpenter syndrome, an autosomal recessive disease which causes cranio-synostosis, obesity and limb malformation.39 RAB7A/RAB7 mutations lead to Charcot‐Marie‐Tooth type 2B disease with sensory loss, distal muscle weakness and high frequency of foot ulcers and infections.40 RAB39B mutations cause X-linked mental retardation and Parkinson’s disease.20, 41-46 Unfortunately, reports describing the genetic association between Rabs and AD are limited: in one study characterizing the genetic association of AD with retromer or retromer-associated proteins in Caucasian samples, RAB7A was identified to be associated with AD.47 The authors also demonstrated that RAB7A interacts with the retromer complex, thereby mediating its association with membranes.47 In another study, "AD resilient" APOE ε4 allele carriers over 75 years of age lacking clinical symptoms of cognitive decline were characterized for genetic factors associated with the lack of AD onset. The authors showed that an SNP (rs142787485) in RAB10 confers significant protection against AD.48 Exome sequencing of LOAD patients and controls also identified significant genetic association of a variant in RAB11A



(rs117150201) with AD.49 In addition to Rab GTPases, GWAS analyses also implicated a RAB5 guanine nucleotide exchange factor, RIN3 (Ras and Rab interactor 3) 50-52 as a risk factor for AD onset.32-34 Recently, a missense variant in the RIN3 gene was found to be associated with EOAD.53 Despite the genetic implications of these findings, whether these Rab GTPases and regulators have a causal role in AD pathogenesis (Class A) requires further corroboration.

4. ALTERATIONS OF RAB GTPASES IN AD Gene expression and/or protein levels of multiple Rab GTPases have been found to be altered in samples from AD patients, and also in animal and cell models. However, whether such changes contribute to disease progression, or merely signify downstream effects accompanying AD is difficult to ascertain. There is evidence suggesting that Rab GTPases may also be perturbed by AD toxicity. For instance, neuronal internalization of Aβ can trigger neurodegeneration accompanied by increased levels and/or altered distribution of RAB5 and RAB7.54 It is likely that Rab GTPases which regulate Aβ and/or tau and undergo early changes in expression and/or distribution contribute to AD progression (Class B). Rab GTPases that show changes late in AD onset which have no effect on modulating Aβ and/or tau may represent downstream effectors in AD pathogenesis (Class C). RAB5 may be the most extensively characterized Rab GTPase of all family members. By interacting with various effectors, RAB5 regulates tethering and fusion of early


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endosomes, endosomal membrane trafficking, and endosomal sorting and fusion.21-24, 55, 56

RAB5-positive early endosomes are significantly enlarged in AD brain and are

associated with elevated levels of the recycling marker RAB4,57 signifying that both endocytic uptake and recycling are activated in AD.27 One study characterizing AD-associated gene expression in CA1 neurons determined that levels of RAB4A/RAB4, RAB5, RAB7 (involved in late endosomes58), and RAB24 (involved in autophagy59) were significantly up-regulated in mild cognitive impairment (MCI) and AD individuals.28 In cholinergic basal forebrain neurons microdissected from postmortem

brains

of

MCI

and

AD

patients,

RAB4,

RAB5,

RAB7,

and RAB27A/RAB27 (involved in exocytosis, endocytosis and phagocytosis60) were found to be upregulated, and their expression correlated with antemortem measures of cognitive decline.61 Selective upregulation of RAB5 and RAB7 levels was observed within basal forebrain, frontal cortex and hippocampus in MCI and AD, which also correlated with advanced Braak staging.62 Additionally, RAB7 levels were found to be elevated in the frontal cortex region in rapid progressive AD forms.63 RAB10 plays an important role in the exocytosis/secretory pathway and may be involved in neurotransmitter release and phagosome maturation.64 In addition to its genetic association with AD, RAB10 expression was also found to be significantly increased in human AD brain; and downregulation of RAB10 resulted in a significant decrease in Aβ42 levels and in the Aβ42/Aβ40 ratio in neuroblastoma cells.48 Another study also determined that the expression of RAB10 as well as its microRNA regulator,



miRNA-655, were both altered in AD samples.65 One recent study found that RAB10 phosphorylation at threonine 73 was prominent in NFTs in neurons within the hippocampus of AD cases when compared to controls, suggesting that RAB10 phosphorylation might also be involved in AD.66 Given that Rab GTPases often regulate synaptic function, it is not surprising that levels of RAB3A are enriched in presynaptic vesicles and its levels were found to be markedly decreased in the frontal and parietal cortices of AD specimens, which correlated with cognitive impairment in AD.67 RAB8A/RAB8 is an important regulator of polarized trafficking and is involved in trans-Golgi network (TGN)-basolateral plasma membrane trafficking, protrusion formation and ciliogenesis.68-70 RAB8 levels were significantly increased in the membrane fractions from AD brain tissues compared to controls.71 RAB6A/RAB6 is involved in retrograde Golgi-ER trafficking and was found to be upregulated in the temporal cortex of Braak stage 3/4 AD brains.72 Extensive alterations in Rab family members in AD brain highlight the contribution of Rab GTPase dysregulation to AD and support the idea that endosomal pathology may promote aberrant trafficking, signaling, and neurodegeneration throughout the progression of AD.

5. A ROLE FOR RAB GTPASES IN APP PROCESSING The finding that the majority of Rab GTPase levels are increased in AD is consistent with


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the idea that enhanced endocytosis may promote Aβ production and accumulation in early stages of AD onset.27, 73 Aβ is derived from APP through sequential cleavage events by BACE1 and γ-secretase. Amyloidogenic cleavage occurs predominantly in intracellular compartments such as early endosomes, late endosomes and the TGN.74-76 Therefore, sorting APP and its cognate secretase enzymes into coincident compartments to initiate Aβ production involves the participation of endocytic regulators including Rab GTPases. On the other hand, α-secretases cleave APP primarily at the cell surface such that changes in trafficking may also interfere with APP α-cleavage, leading to alterations in β-cleavage.

5.1. Rab-Mediated Regulation of APP Trafficking Nascent APP is transported via the secretory pathway through the endoplasmic reticulum (ER) and the TGN apparatus to the plasma membrane. APP is then either cleaved by α-secretase to produce sAPPα or re-internalized into early endosomes. APP in early endosomes can either be recycled back to the cell surface or be delivered to late endosomes and lysosomes for degradation.77-79 Multiple Rab GTPases have been implicated in regulating APP trafficking. For example, RAB1B regulates vesicular transport between the ER and successive Golgi compartments.80 In a study on APP anterograde transport, RAB1B was found to play a key role in APP trafficking from the ER to Golgi: a dominant-negative RAB1B mutant blocked APP ER/Golgi transport and significantly inhibited Aβ secretion.81 Another study



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found that during APP anterograde transport, APP was present in vesicles containing kinesin-1C (a kinesin heavy chain isoform), ADAM10 (an α-secretase) and RAB3A. Further, RAB3A GTPase was shown to be necessary for the assembly of these vesicles.82 RAB6 is localized in the late Golgi apparatus and is involved in retrograde transport from the Golgi apparatus to the ER, transport of early endosomes and recycling endosomes to TGN, and vesicle exocytosis.83-87 One study found that RAB6 may function as a negative regulator of APP anterograde trafficking through the TGN or as a positive modulator of APP retrograde trafficking back to the TGN. A dominant-negative RAB6 mutant may promote anterograde trafficking of APP through the secretory pathway to promote α-secretase-mediated cleavage.88 The function of RAB6 in modulating APP processing may be mediated through its interaction with Mint family proteins,89, 90 which have been shown to fine-tune APP trafficking and processing by binding to the APP YENPTY motif.91, 92 In addition, RAB6 was found to modulate the unfolded protein response, suggesting that increased RAB6 levels in AD brain may result in a failure to recover from ER stress, thereby contributing to neurodegeneration in AD.72, 93

Rab11

proteins

comprise

related

proteins,

RAB11A,

RAB11B

and

RAB11C/RAB25.94 They direct exocytosis and recycling processes, thereby regulating secretion and plasma membrane composition.94, 95 Interestingly, RAB11B has been found to colocalize to some extent with APP in axons.96 Knockdown of RAB11B led to defects in soma‐to‐axon transcytosis of APP in neurons.97


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The amyloid precursor-like protein (APL-1) is the sole APP ortholog in Caenorhabditis elegans. RAB5 knockdown also dramatically decreased APL-1 expression in neurons, suggesting that retrograde trafficking from the plasma membrane to early endosomes is important for APL-1 function.98

5.2. Rab GTPases and BACE1 As the predominant β-secretase for APP, BACE1 initiates APP processing in acidified endosomes, where BACE1 is found to possess maximal enzymatic activity. Imaging analysis revealed that BACE1 was localized and transported along dendrites and axons in RAB11B-positive recycling endosomes. Impairment of RAB11B function led to a diminution of total and endocytosed BACE1 in axons, concomitant with increased BACE1 in the soma. These results suggest that RAB11B function is critical for axonal sorting of BACE1.99 In a human Rab RNAi screening for Aβ modulators, downregulation of RAB3A, RAB11A, RAB17 (involved in phagocytic removal of apoptotic cells100), and RAB36 (involved in late endosome and lysosome distribution101) reduced both Aβ and sAPPβ, implicating a potential role for these factors in modulating BACE1.49 Consequent studies validated a role for RAB11A and its homolog RAB11B in regulating β-cleavage and Aβ generation through controlling BACE1 membrane trafficking and recycling.49

5.3. Rab GTPases and PS1



PS1 is the most extensively characterized component of the γ-secretase complex and functions as its catalytic center. PS1 may also exert other γ-secretase-independent functions by interacting with effector proteins. Although PS1 can interact with RAB11A,102 whether PS1 trafficking is regulated by RAB11A or other Rab proteins has yet to be established. Overexpression of RAB11A has no effect on APP processing in HEK293 cells.103 However, the possibility remains that RAB11A may still modulate other aspects of PS1-dependent function. On the other hand, it seems likely that PS1 may have an upstream role in regulating the function of Rab GTPases and Rab-related proteins. It has been reported that membrane association of RAB6 but not RAB1 is dependent on PS1.104 The PS1 amino-terminus was found to interact with Rab GDI, and membrane-associated Rab GDI levels were found to be dramatically decreased in the absence of PS1.105 These findings imply that PS1 may be a membrane receptor for certain Rabs and Rab-related proteins. In cells expressing fAD-associated PS1 mutants (G384A and I143T), and in neurons from 3xTg-AD mice, RAB4 and RAB6 levels were found to be increased.106 In contrast, RAB8 levels were decreased in cells expressing a PS1 mutant (A260V).107 Moreover, in human iPSC-derived neurons carrying a fAD PS1 mutation (∆E9), RAB11B distribution was altered in a manner similar to APP.97 Therefore, PS1 mutations may perturb Rab proteins and membrane vesicle transport, thereby facilitating amyloidogenic APP processing and Aβ generation through γ-cleavage-independent pathways.


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5.4. Rab GTPases and α-secretases Several type I transmembrane ADAM family proteins have been found to possess α-secretase activity. Among them, ADAM10 is believed to be the constitutive α-secretase that is active at the cell surface.16, 108 Other α-secretases, such as ADAM17 and ADAM9 affect only regulated α-cleavage in various cell lines.109, 110 RAB14 functions in the endocytic recycling pathway and is involved in trafficking between the Golgi and endosomal compartments.111, 112 It was found that RAB14 can regulate ADAM10 recycling: its depletion resulted in ADAM10 accumulation in a transferrin-positive endocytic compartment, accompanied by reduced cell-surface levels of ADAM10.113, 114 In addition, another study found that downregulation of RAB11A could reduce cell surface expression of ADAM17.115 Hence, aberrations in various Rab GTPase family proteins may indirectly affect Aβ production, implicating their potential contributions in AD.

6. RAB GTPASES AND Aβ DEGRADATION/AGGREGATION Aggregation of Aβ peptides leads to synaptic disruption and neurodegeneration. A major clearance pathway for extracellular Aβ is through cellular uptake and degradation. One study demonstrated that endocytic Aβ internalized in neurons trafficked primarily via early and late endosomes to the lysosome; and lysosomal inhibition resulted in Aβ accumulation and aggregation.116 In addition, endocytosed Aβ caused multivesicular body enlargement in neurons and generated fibril-like structures in endocytic vesicles.117 On



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the other hand, overexpression of either the early endosome protein RAB5 or the late endosome protein RAB7 accelerated endocytic Aβ trafficking to the lysosome.116 Moreover,

a

proportion

of

endocytically

internalized

Aβ

was

observed

in

RAB11A-positive recycling vesicles. Use of a constitutively active RAB11A mutant to block this recycling significantly accelerated cellular Aβ accumulation.116 Allelic variation in the APOE gene is the strongest risk factor for LOAD. In addition to transporting cholesterol in the brain, apoE also participates in Aβ degradation and the reduction of cellular cholesterol levels by apoE leads to accelerated Aβ delivery to lysosomes to enhance its degradation.118 Moreover, apoE facilitates the recycling of RAB7 from lysosomes to early endosomes, suggesting that efficient RAB7 recycling may accelerate faster endocytic trafficking of Aβ-containing vesicles and enhance Aβ degradation.118 The assembly of soluble Aβ to Aβ fibrils in senile plaques is a critical event in AD. Although abnormalities in the endocytic pathway precede extracellular Aβ fibril deposition in the brain,27 blocking the early endocytic pathway by RAB5 depletion did not lead to fibril formation on the cell surface with exogenous addition of soluble Aβ. In contrast, blocking the late endocytic pathway by RAB7 suppression markedly induced Aβ fibril formation and enlargement of early endosomes. These results suggest that dysfunction of late, rather than early, endocytic mechanisms contribute to Aβ fibril formation, possibly by facilitating the generation of Aβ seeds in AD brain.119


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7. RAB GTPASES AND TAU SECRETION The microtubule‐associated protein tau can be released into the extracellular space, possibly via exosomes, and subsequently resorbed by neurons and glial cells, an event that has been proposed to contribute to the propagation of tau pathology.120-123 Recently it was found that RAB7A, involved in the trafficking of endosomes, autophagosomes and lysosomes, can also regulate tau secretion. Deletion of RAB7A and overexpression of a dominant negative form of RAB7A decreased tau secretion, whereas overexpression of a constitutively active form of RAB7A showed converse effects.124 Elevated RAB7A levels in human AD brains and brains from AD mouse models, as well as colocalization between RAB7A and tau, suggests that RAB7A may contribute to tau propagation in AD.63, 124 Neuronal hyperexcitability can promote tau release by neurons and induce Golgi fragmentation. RAB1A is associated with Golgi membranes and its suppression is known to induce Golgi fragmentation. One study found that suppression of RAB1A also increased tau secretion.125 Although the underlying mechanism remains elusive, this indicates that Rab-mediated Golgi dynamics can modulate tau secretion.

8. POTENTIAL USE OF RAB GTPASES IN AD DIAGNOSTICS The success of future AD therapeutics will likely rely on the development of treatment strategies targeting early stages of AD onset, prior to late stage events associated with irreversible brain damage. Neuronal degeneration is observed long before the clinical



onset, highlighting the need for biomarkers that can be used for early diagnosis in AD. Since Aβ and tau are major components of AD pathology, they are key indicators of AD pathogenesis. Indeed, it has gradually become accepted that Aβ42 levels are decreased, whereas total tau and phosphorylated-tau levels are increased in cerebrospinal fluid (CSF) of AD patients in early clinical stages when compared to control individuals. This suggests that changes in Aβ42 and total tau/phosphorylated-tau levels may be viable biomarkers in the early diagnosis of AD.126, 127 By using ultra-sensitive techniques, it has recently been noted that both Aβ and phosphorylated tau levels in plasma from AD patients also show differences compared to controls.128, 129 The microglia-enriched innate immune receptor TREM2 has been previously described as a potent genetic risk factor in AD.130-132 Recently, levels of soluble TREM2 (sTREM2) derived from proteolytic TREM2 ectodomain cleavage were found to be increased and correlated with total tau and phosphorylated-tau in CSF from MCI and AD patients. Levels of sTREM2 were also found to be increased in CSF from fAD mutation carriers compared to non-carriers.133, 134 These results suggest that sTREM2 may be a viable early AD biomarker. Changes in the endo-lysosomal network are among the first alterations observed in the AD brain, and characterization of proteins within the endo-lysosomal network in human CSF indicated that RAB3A and RAB7 levels were markedly increased in AD patient samples compared to controls.135 Therefore, further characterization of changes in RAB3 and RAB7 levels in the CSF as well as the plasma from AD patients may determine whether they can be used as viable AD biomarkers and evaluate endo-lysosomal dysfunction during AD


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development.

9. THERAPEUTIC POTENTIAL OF RAB GTPASES Dysregulation of the endo‐lysosomal system is an early cellular phenotypic event in AD pathogenesis. Treatment with the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK) in AD mouse models increased cathepsin B protein levels and enzymatic activity, increased Aβ truncation and reduction, and consequently reversed impairments in animal behaviors and synaptic proteins. Biochemical analysis revealed marked changes to Rab proteins but not to LAMP1 upon PADK treatment, suggesting the role of trafficking modulation during rescue.136 In addition, epidemiological studies suggest that statins may reduce the risk of AD through undetermined mechanisms. One study found that fluvastatin at clinical doses resulted in significant reductions in Aβ and APP βCTF levels, but this effect was abolished with the additive treatment of lysosomal inhibitors. Further analysis indicated that reduced Aβ production was caused by enhanced lysosomal degradation of APP βCTF. This effect arose from enhanced endosomal APP βCTF trafficking to lysosomes, and it was associated with marked changes in Rab proteins.137 Taken together, these findings demonstrate that lysosomal modulation can reduce Aβ accumulation and improve behavioral impairment, suggesting that targeting Rab GTPases may be a viable therapeutic target in AD.

10. CONCLUDING REMARKS



Rab GTPases are implicated in multiple pathological mechanisms in AD (Table 1). Interestingly, many AD-associated proteins identified thus far play roles in trafficking pathways, some of which are linked to Rab proteins. For instance, PICALM plays an important role in regulating Aβ internalization, trafficking and clearance via the low‐ density lipoprotein receptor‐related protein‐1 and Rab proteins (RAB5 and Rab11 members).138,

139

Dysregulation of AD-associated proteins and Rab GTPases perturbs

endosomal, lysosomal, recycling and autophagic pathways. Further elucidation of the complex physiological function of Rab GTPases and their pathological roles in AD holds great potential for developing novel therapeutics in disease intervention.


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AUTHOR INFORMATION Corresponding Author *E-mail: [email protected].

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Funding This work was supported in part by grants from The National Key Research and Development Program of China (2016YFC1305903), The National Natural Science Foundation of China (81771377 and U1705285 to Y-w.Z.) and Fundamental Research Funds for the Central Universities (20720180049 to Y-w.Z.).

Notes The authors declare no competing financial interest.



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Table 1. Summary of Rab GTPases associated with AD Rab GTPase Reported/proposed

Categoriesa

Association with AD

functions RAB1A

Mediates Golgi dynamics Affects tau secretion125

RAB1B

Regulates

ER-Golgi Affects APP trafficking and B

vesicular transport RAB3A

B

Aβ generation81

Localizes in presynaptic Decreased in AD brain67; vesicles

and

exocytosis

B, C

regulates Increased in AD CSF135; Affects APP assembly into anterograde

transporting

vesicles82; Affects APP β-cleavage and Aβ generation49 RAB4

Regulates recycling

endosomal Increased in AD brain and C neurons28, 57, 61, in AD mice and

in

cells

expressing

fAD-associated

PS1

mutants106 RAB5A/RAB

Modulates

endosomal Increased in AD brain and B, C

5

membrane

trafficking, neurons28, 57, 61, 62;



Page 48 of 53

sorting and endosomal Affects APL-1 expression98; fusion

Accelerates endocytosed Aβ trafficking

to

the

lysosome116; Related

to

PICALM-mediated internalization,

Aβ

trafficking

and clearance138, 139; Levels/distribution affected by Aβ54 RAB6A/RA

Regulates

B6

Golgi-ER transport

retrograde Increased in AD brain72, in B, C trafficking, AD of

mice

early expressing

and

in

cells

fAD-associated

endosomes and recycling PS1 mutants106; endosomes to the TGN, Affects APP trafficking and and vesicle exocytosis

Aβ generation88; Modulates

AD-related

unfolded protein response72, 93

;

Membrane


association

Page 49 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


dependent on PS1104 RAB7A/RAB

Controls transport to late Genetic association47;

7

endosomes lysosomes

A, B, C

and Increased in AD28, 61-63; Increased in AD CSF135; Affects

Aβ-containing

vesicle endocytic trafficking and Aβ degradation116, 118 Affects

Aβ

fibril

formation119; Levels/distribution affected by Aβ54; Regulates tau secretion124 RAB8A/RA

Modulates

polarized Increased

B8

trafficking

decreased

in

AD71 in

but B, C cells

expressing a PS1 mutant (A260V) 107 Accelerates endocytosed Aβ trafficking

to

the

lysosome116 RAB10

Modulates

Genetic association48;


A, B, C


Page 50 of 53

exocytosis/secretory

Increased in AD48, 65;

pathway,

Phosphorylated RAB10 (at

neurotransmitter release threonine 73) is prominent and maturation

phagosome in AD neuron NFTs66; Affects

Aβ42

and

Aβ42/Aβ40 ratio48 RAB11A

Regulates both endocytic Genetic association49; and exocytic trafficking Regulates pathways

A, B, C

BACE1

membrane trafficking and recycling

and

Aβ

generation49, 99; Interacts with PS1102; Affects

endocytosed

Aβ

trafficking116; Affect cell surface levels of ADAM17115; Related

to


trafficking

and clearance138, 139


Aβ

Page 51 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


RAB11B

Regulates both endocytic Colocalizes with APP and B and exocytic trafficking affects pathways

soma‐to‐axon

transcytosis

of

APP

in

neurons96, 97; Regulates

BACE1

membrane trafficking and recycling

and

Aβ

generation49, 99; Related

to


Aβ

trafficking

and clearance138, 139 RAB14

Involved

in

endocytic Affects

ADAM10 B, C

and recycling113, 114

recycling Golgi-endosome trafficking RAB17

Involved in phagocytic Affects APP β-cleavage and B removal

of

apoptotic Aβ generation49

cells RAB24

Involved in autophagy

Increased in AD28


C


RAB27A/RA Regulates B27

Page 52 of 53

exocytosis, Increased in AD61

endocytosis

C

and

phagocytosis RAB36

involved

in

late Affects APP β-cleavage and B

endosome and lysosome Aβ generation49 distribution RIN3

A

guanine

exchange

nucleotide Genetic association32-34, 53 factor

A

for

RAB5 Rab GDI

Promotes GTP hydrolysis Membrane

association B, C

to Inactivate GTP-bound affected by PS1105 GTPases a

Classification based on Kiral et al.29


Page 53 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Rab GTPases and AD 80x39mm (300 x 300 DPI)


The Role of Rab GTPases in Alzheimer's Disease - ACS Chemical

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