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COMMUNICATION ARTICLE
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
Australia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-0521.94982

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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 2019 Jul 21];1:35-7. Available from: http://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)

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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.

 
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