Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 
    Users Online: 75
Home Print this page Email this page Small font size Default font size Increase font size

 Table of Contents  
Year : 2012  |  Volume : 1  |  Issue : 1  |  Page : 35-37  

Elucidating the molecular mechanisms that govern β-Amyloid protein-induced neuritic dysfunction in Alzheimer's disease

Monash Immunology and Stem Cell Laboratories, Monash University, Clayton Victoria, Australia

Date of Web Publication13-Apr-2012

Correspondence Address:
Steven Petratos
Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Melbourne, Victoria, 3800
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2278-0521.94982

Rights and Permissions

How to cite this article:
Petratos S, Azari MF, Cram D. Elucidating the molecular mechanisms that govern β-Amyloid protein-induced neuritic dysfunction in Alzheimer's disease. Saudi J Health Sci 2012;1:35-7

How to cite this URL:
Petratos S, Azari MF, Cram D. Elucidating the molecular mechanisms that govern β-Amyloid protein-induced neuritic dysfunction in Alzheimer's disease. Saudi J Health Sci [serial online] 2012 [cited 2021 Oct 28];1:35-7. Available from: https://www.saudijhealthsci.org/text.asp?2012/1/1/35/94982

Alzheimer's disease (AD) is the most common form of dementia in the elderly. The disease is characterized by a gradual loss of memory over several years duration. It is estimated that approximately 5-10% of the population over the age of 65 have at least some clinical features of AD. Of major significance to the aging population in the western world, is the prediction that the percentage of people with AD is expected to rise over the next 20 years. Considering the quality of life of our elderly and the cost of care for one person with AD is estimated to be $US 300,000, development of an effective therapy for AD is urgently needed.

Neurologically, AD is a type of dementia characterized by progressive cognitive decline, memory loss and confusion, both in the disease's familial and sporadic forms. The major pathological hallmark of AD is the well-defined presence of proteinaceous deposits in the brain, as amyloid plaques (APs) and cerebral amyloid angiopathy. There are also, intracellular hyperphosphorylated tau-positive neurofibrillary tangles (NFTs). [1] Extracellular APs consist of a 4-kDa polypeptide known as the β-amyloid protein (Aβ), which is derived from a much larger β-amyloid protein precursor (APP) [Figure 1]. Cleavage of APP by β- and γ-secretases generates Aβ, which is subsequently secreted into the extracellular environment. [2],[3],[4] The major form of Aβ is produced after cleavage by γ-secretase at position 40 in the Aβ sequence (Aβ1-40). However, a minor cleavage at position 42 produces long Aβ (or Aβ1-42), which is 42 amino-acid residues in length. [2]
Figure 1: Structure of amyloid protein precursor, which contains an N-terminus cysteine-rich domain. Proteolytic cleavage sites (arrows)

Click here to view

Because of its propensity to aggregate, Aβ builds up in the brain and assembles into amyloid fibrils, ultimately creating APs. [5] There is now strong evidence that the formation of oligomeric Aβ is a key event in the pathogenesis of AD. Oligomeric Aβ has been shown to be toxic to neurons in culture. [6] However, the mechanism by which Aβ causes cognitive decline is unclear. We are currently deciphering the molecular basis of Aβ-mediated neurite dystrophy with the aim of developing strategies to combat the cognitive decline in AD.

Neurite outgrowth and dystrophy in Alzheimer's disease

Neurite dystrophy is characterized by swollen axons or dendrites surrounding APs, which show strong immunoreactivity for neurofilament, tau or chromogranin A. These neurites display an abnormal morphology as bulbous or ring-like structures, which are related to their aberrant growth in the presence of Aβ. [7] Dystrophic neurites can be seen in areas of synaptic loss in the hippocampal formation and neocortex [8],[9] and are characteristically seen in AD brains at autopsy, typically associated with Aβ deposition. [1],[10] Aβ has been reported, to induce neurite dystrophy in culture [11] as well as in mutant mouse models of AD. [8],[9] Recent evidence suggests a dynamic functional decline of the neuron in which Aβ causes progressive neuronal dystrophy and synaptic loss, occurring at an early stage, followed by a gradual decline in neuronal viability. [12] Neuronal dysfunction and cognitive decline in AD, can be defined as, a loss of neural networks through abnormal synaptic plasticity, a direct result of Aβ toxicity on neuritis. [13] These neuritic changes in neurons of the frontal and temporal cortices manifest initially as mild cognitive impairment (MCI), followed by more severe memory loss as the disease progresses. [10] One definitive aspect of Aβ-mediated neurite dystrophy is the reduction in length and calibre of the neurite, seen both in culture and in vivo, [8],[14] i.e. Aβ can mediate neurite outgrowth inhibition. [15] Our data clearly implicate the small Rho-GTPases as effector molecules in neuritic dysfunction initiated by Aβ-signalling. [15]

Aβ activates RhoA initiating neurite outgrowth inhibition

The molecular regulation of neurite outgrowth is governed by the Rho-GTPases and involves positive and negative signals on microfilaments and microtubules, for directional and contact growth. [16],[17],[18] As an intracellular effector of neurite retraction, the role of RhoA-GTP (active RhoA) in neurological disease paradigms has been well established. [19] The primary function of RhoA at the synapse may involve decreased dendritic spine outgrowth (morphogenesis) during development by regulating spine microfilament (actin/myosin) dynamics. [20] Our novel finding that, Aβ oligomers reduce neurite outgrowth by activating RhoA (RhoA-GTP) [15] suggests that signalling through RhoA-GTP may be an important mechanism initiating neuritic dystrophy in AD. We also reported for the first time that, the Aβ-mediated activation of RhoA induced phosphorylation of the collapsin response mediator protein 2 (CRMP-2). [15]

Aβ induces phosphorylation of collapsin response

mediator protein-2 altering neuronal microtubule dynamics

CRMPs are a family of neuronal phosphoproteins, [21] which regulate microtubule assembly as well as anterograde vesicular transport of important growth-related molecular cargo along neuronal microtubules. [22],[23] CRMP-2 has already been shown to be phosphorylated by cyclin-dependent kinase 5 (Cdk-5) at Ser522, [24],[25] glycogen synthase kinase 3β (GSK-3β) at Thr514/509/Ser 518 [26],[27] and also Rho kinase at Thr555, [28],[29] all of which can mediate neurite retraction. Such phosphorylation disrupts the association of CRMP-2 with tubulin heterodimers, so that tubulin cannot be transported to the plus ends of microtubules for assembly, impeding directional growth of the neurite. [22] Importantly, phosphorylation of CRMP-2 reduces its binding to kinesin-1 microtubule-related motor protein. [30] Since, kinesin-1 is involved in anterograde vesicular axonal transport of molecules involved in synaptic integrity and plasticity (eg. BDNF) to the distal ends of axons, [30] phosphorylation of CRMP-2 is expected to alter microtubule dynamics.

We were the first to show that, extracellular administration of Aβ can increase the level of phosphorylation of a threonine residue on CRMP-2. [15] Furthermore, the threonine phosphorylation of CRMP-2 occurred concomitantly with Aβ-dependent RhoA activation and could be inhibited by a specific Rho kinase inhibitor (Y27632). Moreover, Y27632 administration to SH-SY5Y cells prevented neurite outgrowth inhibition induced by Aβ.[15] Taken together, our results indicate that Aβ-activated Rho kinase initiates phosphorylation of CRMP-2. Moreover, our results suggest that Aβ-induced phosphorylation of CRMP-2 regulates neurite outgrowth inhibition. Our current research aims to (i) identify the Aβ-induced phosphorylation site in CRMP-2 and (ii) examining the validity of this notion.

In the Tg2576 mouse model of AD, the levels of RhoA-GTP and CRMP-2 threonine phosphorylation are increased at 12 and 18 months-of-age correlating with the formation of neuritic dystrophy and increasing levels of Aβ in the brain. [15] Collectively, these data suggest a Rho kinase-dependent mechanism by which extracellular Aβ oligomers potentiate neurite outgrowth inhibition. Despite the presence of other phosphorylated forms of CRMP-2 being identified recently in the cortex of AD brains and in the Tg2576 model, they were not significantly elevated above control. [31] Moreover, the relationship between Aβ-mediated neurite dysfunction and the other phosphorylated forms of CRMP-2 (i.e. Thr509/514 and Ser522) has not been defined. It is now important to define, whether the ROCK II/CRMP-2 mechanism is the dominant pathway leading to Aβ-induced neurodegeneration, or whether the other kinases (Cdk-5 and GSK-3β) involved in CRMP-2 phosphorylation also play a significant role.

  References Top

1.Small DH, McLean CA. Alzheimer's disease and the amyloid beta protein: What is the role of amyloid? J Neurochem 1999;73:443-9.  Back to cited text no. 1
2.De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998;391:387-90.  Back to cited text no. 2
3.Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999;402:537-40.  Back to cited text no. 3
4.Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999;286:735-41.  Back to cited text no. 4
5.Walsh DM, Hartley DM, Kusumoto Y, Fezoui Y, Condron MM, Lomakin A, et al. Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J Biolog Chem 1999;274:25945-52.  Back to cited text no. 5
6.Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 2005;280:17294-300.  Back to cited text no. 6
7.Knowles RB, Gomez-Isla T, Hyman BT. Abeta associated neuropil changes: Correlation with neuronal loss and dementia. J Neuropathol Exp Neurol 1998;57:1122-30.  Back to cited text no. 7
8.Tsai J, Grutzendler J, Duff K, Gan WB. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosc 2004;7:1181-3.  Back to cited text no. 8
9.Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, et al. Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci 2005;25:7278-87.  Back to cited text no. 9
10.Näslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 2000;283:1571-7.  Back to cited text no. 10
11.Heredia L, Helguera P, de Olmos S, Kedikian G, Solá Vigo F, LaFerla F, et al. Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid beta-induced degeneration: A potential mechanism of neuronal dystrophy in Alzheimer's disease. J Neurosci 2006;26:6533-42.  Back to cited text no. 11
12.Spires TL, Hyman BT. Neuronal structure is altered by amyloid plaques. Rev Neurosci 2004;15:267-78.  Back to cited text no. 12
13.Small DH. Do acetylcholinesterase inhibitors boost synaptic scaling in Alzheimer's disease? Trends Neurosci 2004;27:245-9.  Back to cited text no. 13
14.Postuma RB, He W, Nunan J, Beyreuther K, Masters CL, Barrow CJ, et al. Substrate-bound beta-amyloid peptides inhibit cell adhesion and neurite outgrowth in primary neuronal cultures. J Neurochem 2000;74:1122-30.  Back to cited text no. 14
15.Petratos S, Li QX, George AJ, Hou X, Kerr ML, Unabia SE, et al. The β-amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism. Brain 2008;131:90-108.  Back to cited text no. 15
16.Buck KB, Zheng JQ. Growth cone turning induced by direct local modification of microtubule dynamics. J Neurosci 2002;22:9358-67.  Back to cited text no. 16
17.Yuan XB, Jin M, Xu X, Song YQ, Wu CP, Poo MM, et al. Signalling and crosstalk of Rho GTPases in mediating axon guidance. Nat Cell Biol 2003;5:38-45.  Back to cited text no. 17
18.Zhang XF, Schaefer AW, Burnette DT, Schoonderwoert VT, Forscher P. Rho-dependent contractile responses in the neuronal growth cone are independent of classical peripheral retrograde actin flow. Neuron 2003;40:931-44.  Back to cited text no. 18
19.Mueller BK, Mack H, Teusch N. Rho kinase, a promising drug target for neurological disorders. Nat Rev Drug Discov 2005;4:387-98.  Back to cited text no. 19
20.Sfakianos MK, Eisman A, Gourley SL, Bradley WD, Scheetz AJ, Settleman J, et al. Inhibition of Rho via Arg and p190RhoGAP in the postnatal mouse hippocampus regulates dendritic spine maturation, synapse and dendrite stability, and behavior. J Neurosci 2007;27:10982-92.  Back to cited text no. 20
21.Hamajima N, Matsuda K, Sakata S, Tamaki N, Sasaki M, Nonaka M. A novel gene family defined by human dihydropyrimidinase and three related proteins with differential tissue distribution. Gene 1996;180:157-63.  Back to cited text no. 21
22.Fukata Y, Itoh TJ, Kimura T, Ménager C, Nishimura T, Shiromizu T, et al. CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat Cell Biol 2002;4:583-91.  Back to cited text no. 22
23.Quinn CC, Chen E, Kinjo TG, Kelly G, Bell AW, Elliott RC, et al. TUC-4b, a novel TUC family variant, regulates neurite outgrowth and associates with vesicles in the growth cone. J Neurosci 2003;23:2815-23  Back to cited text no. 23
24.Uchida Y, Ohshima T, Sasaki Y, Suzuki H, Yanai S, Yamashita N, et al. Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3 beta phosphorylation of CRMP2: Implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease. Genes to Cells 2005;10:165-79.  Back to cited text no. 24
25.Cole AR, Causeret F, Yadirgi G, Hastie CJ, McLauchlan H, McManus EJ, et al. Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo. J Biol Chem 2006;281:16591-8.  Back to cited text no. 25
26.Cole AR, Knebel A, Morrice NA, Robertson LA, Irving AJ, Connolly CN, et al. GSK-3 phosphorylation of the Alzheimer epitope within collapsing response mediator proteins regulates axon elongation in primary neurons. J Biol Chem 2004;279:50176-80.  Back to cited text no. 26
27.Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K. GSK-3 beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 2005;120:137-49.  Back to cited text no. 27
28.Arimura N, Inagaki N, Chihara K, Ménager C, Nakamura N, Amano M, et al. Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse. J Biol Chem 2000;275:23973-80.  Back to cited text no. 28
29.Arimura N, Ménager C, Kawano Y, Yoshimura T, Kawabata S, Hattori A, et al. Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones. Mol Cell Biol 2005;25:9973-84.  Back to cited text no. 29
30.Kawano Y, Yoshimura T, Tsuboi D, Kawabata S, Kaneko-Kawano T, Shirataki H, et al. CRMP-2 is involved in kinesin-1-dependent transport of the Sra-1/WAVE1 complex and axon formation. Mol Cell Biol 2005;25:9920-35.  Back to cited text no. 30
31.Cole AR, Noble W, van Aalten L, Plattner F, Meimaridou R, Hogan D, et al. Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression. J Neurochem 2007;103:1132-44.  Back to cited text no. 31


  [Figure 1]

This article has been cited by
1 Drebrin and cognitive impairment
Lina Ma,Yun Li,Rong Wang
Clinica Chimica Acta. 2015; 451: 121
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
   Article Figures

 Article Access Statistics
    PDF Downloaded372    
    Comments [Add]    
    Cited by others 1    

Recommend this journal