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Review
. 2014 Sep 5:5:279.
doi: 10.3389/fgene.2014.00279. eCollection 2014.

Use of Caenorhabditis elegans as a model to study Alzheimer's disease and other neurodegenerative diseases

Adanna G Alexander  1 , Vanessa Marfil  2 , Chris Li  1
Affiliations
Review

Use of Caenorhabditis elegans as a model to study Alzheimer's disease and other neurodegenerative diseases

Adanna G Alexander et al. Front Genet. .

Abstract

Advances in research and technology has increased our quality of life, allowed us to combat diseases, and achieve increased longevity. Unfortunately, increased longevity is accompanied by a rise in the incidences of age-related diseases such as Alzheimer's disease (AD). AD is the sixth leading cause of death, and one of the leading causes of dementia amongst the aged population in the USA. It is a progressive neurodegenerative disorder, characterized by the prevalence of extracellular Aβ plaques and intracellular neurofibrillary tangles, derived from the proteolysis of the amyloid precursor protein (APP) and the hyperphosphorylation of microtubule-associated protein tau, respectively. Despite years of extensive research, the molecular mechanisms that underlie the pathology of AD remain unclear. Model organisms, such as the nematode, Caenorhabditis elegans, present a complementary approach to addressing these questions. C. elegans has many advantages as a model system to study AD and other neurodegenerative diseases. Like their mammalian counterparts, they have complex biochemical pathways, most of which are conserved. Genes in which mutations are correlated with AD have counterparts in C. elegans, including an APP-related gene, apl-1, a tau homolog, ptl-1, and presenilin homologs, such as sel-12 and hop-1. Since the neuronal connectivity in C. elegans has already been established, C. elegans is also advantageous in modeling learning and memory impairments seen during AD. This article addresses the insights C. elegans provide in studying AD and other neurodegenerative diseases. Additionally, we explore the advantages and drawbacks associated with using this model.

Keywords: ALS; Alzheimer’s disease; C. elegans; Parkinson disease; apl-1; model systems.

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Figures

FIGURE 1
FIGURE 1
Similarities and differences between human APP and Caenorhabditis elegans APL-1. (A) Schematic representation of human APP isoforms, other members of the APP family (APLP1 and APLP2), and C. elegans APL-1. (B) Comparison between human APP proteolytic pathways (top) and C. elegans APL-1 proteolytic pathway (bottom). Top. APP can be cleaved by two different pathways. In the anti-amyloidogenic pathway, APP is first cleaved by the α-secretase to release an extracellular fragment sAPPα. The remaining APP fragment (APP-CTFα or C83) is then cleaved by the γ-secretase complex to release p3 extracellularly and the APP intracellular domain (AICD) to the cytosol. In the amyloidogenic pathway, β-secretase first cleaves APP, releasing the sAPPβ fragment. The APP-CTFβ (C99) fragment is subsequently cleaved by the γ-secretase complex, liberating the AICD to the cytosol and Aβ to the lumen. Aβ will aggregate to form amyloid plaques. Bottom. In C. elegans, APL-1 is first cleaved by the α-secretase homologs SUP-17/ADM-4, liberating the extracellular sAPL-1 that is known to regulate worm viability and development. The γ-secretase complex will then cleave the remaining APL-1-CTF to release AICD into the cytosol. General functions of the APP family and APL-1 are indicated.
FIGURE 2
FIGURE 2
Interaction between sAPL-1 and DAF-2 insulin/IGF-1 receptor and DAF-12/NHR pathways. Schematic representation of APL-1 proteolytic pathway and how sAPL-1 may modulate DAF-2 insulin/IGF-1 receptor and DAF-12/NHR signaling pathways. APL-1 is cleaved by the α/γ-secretase pathway in C. elegans. Released sAPL-1 could act as a signaling molecule in the same cell (autocrine regulation) or in neighboring cells (paracrine regulation) to inhibit daf-2 insulin/IGF-1 receptor and daf-12/NHR pathways to affect worm viability and development. The exact mechanism by which sAPL-1inhibits daf-2 insulin/IGF-1 receptor and daf-12/NHR is still unknown and labeled as a question mark (see Ewald et al., 2012b).
FIGURE 3
FIGURE 3
Similarities and differences between human tau and Caenorhabditis elegans PTL-1. (A) Schematic representation of human microtubule binding proteins (MAPs) family, including tau isoforms and C. elegans PTL-1 isoforms. (B) Comparison between tau functions in humans (top) and C. elegans PTL-1/tau functions (bottom). Top. Tau has a physiological role in promoting and maintaining microtubule stability. In pathological conditions tau is hyperphosphorylated and self-aggregates into paired helical filaments (PHFs) that can form intracellular neurofibrillary tangles (NFT). Bottom. C. elegans PTL-1/tau binds microtubules and induces microtubule assembly. It also affects synaptic transport through motor proteins UNC-104/KIF1a/kinesin-3, UNC-116/kinesin-1, and DLC-1/dynein. PTL-1/tau is also important for C. elegans mechanosensation and aging.
FIGURE 4
FIGURE 4
Caenorhabditis elegans as a transgenic model for AD and other neurodegenerative diseases. (A) Summary of the Alzheimer’s disease models in C. elegans expressing human Aβ peptide or C. elegans full-length APL-1 or APL-1 extracellular domain (APL-1 EXT). Arrow color represents the tissues where transgenes were expressed. Phenotypes observed are next to the arrow. (B) Summary of the C. elegans models for Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington’s disease (HD). Genes modeling PD are shown in blue boxes, ALS in pink boxes, FTD in yellow boxes, and HD in green boxes. Arrow color represents tissues where transgenes were expressed. Phenotypes observed are written close to the arrow.
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