The most prevalent form of dementia in the aging population is Alzheimer’s disease (AD), which was first diagnosed in 1906 by the German neuropathologist and psychiatrist, Dr. Alois Alzheimer (Korolev et al., 2014). It was recently declared as the sixth major cause of death worldwide.
Patients with AD suffer from a gradual decline in memory functions and cognitive functions until they become incapable of performing daily activities. Some of these traits, typical of neurodegenerative diseases, are also present in other forms of dementia.
Age and Alzheimer’s Disease
The biggest risk factor for AD is age. As life expectancy increases due to advances in healthcare and medicine, the prevalence of neurodegenerative diseases also increases (Korolev et al., 2014). Research has already provided important insights into many aspects of the mechanism of disease. However, AD is a multifactorial disease and this presents a big challenge with regards to finding a cure.
According to statistical data, there are currently more than 30 million people suffering from AD worldwide. This number is predicted to double every 20 years, reaching 66 million in 2030 and around 115 million in 2050 (ARUK Dementia Facts).
Approximately 95% of AD patients are aged 65 or over at the point of diagnosis and are considered to have “sporadic” or “late-onset AD.” The remaining 5% of AD patients have rare genetic mutations which are associated with “familial” (FAD) or “early-onset AD”, causing the development of the disease before the age of 65. Mutations in the amyloid precursor protein (APP) or presenilin genes account for most of the cases of early-onset AD.
However, the genetics of sporadic AD are more complicated and less well understood. The epsilon four allele of the apolipoprotein E (APOE) gene was discovered as a risk factor for the development of sporadic AD during genome-wide association studies (GWAS) (Bertram et al., 2009).
Recently, a large body of evidence has suggested that family history of diabetes, cerebrovascular risk factors, obesity and hypertension are also important for the development and progression of the disease (Felice et al., 2014).
iPSCs: An Emerging Powerful Translational Model
Extracellular plaques of ß-amyloid and intracellular tangles of hyperphosphorylated tau are two hallmarks of AD pathology. The “ß-amyloid hypothesis” explains the pathogenesis of AD and suggests that the excessive accumulation of amyloid-ß (Aß) triggers a pathological cascade that leads to tau hyperphosphorylation, synaptic dysfunction, neuronal death and neurofibrillary tangles (NFTs).
However, because it is multifactorial by nature, the disease pathogenesis is not well understood. As a result, approved medications for AD are mostly directed at improving neurotransmission for symptomatic control but are unable to halt progression or reverse the disease process.
The neuroscience community has undertaken extensive research into the pathological progression of AD using animal models. However, until now, there have been no preclinical models available that accurately replicate tau tangle and amyloid-plaque pathologies and correlate these markers with progressive impairment of memory. Therefore, many drugs that succeed in preclinical studies fail at the stage of clinical trials.
Induced pluripotent stem cells (iPSCs) are now emerging as powerful translation models for high-throughput drug screening and for investigating complex disease pathways. As a result of recent advances in reprogramming technologies, scientists have created the first FAD neurons from the fibroblasts of patients with AD (Yagi et al., 2011). These iPSCs carrying the FAD mutations and iPSCs derived from sporadic AD patients have an AD genetic background.
This means that they can replicate the markers of early-onset pathogenesis including an increase in endoplasmic reticulum (ER) and oxidative stress and the accumulation of toxic Aß species (Israel et al., 2012). The two dimensional iPSC cultures are not able to replicate the physiological environment of the human brain and so expressed lower levels of 4R tau isoforms and Aß than AD brains.
3D Neural Cell Culture Model: Methodology and Observations
Mudher and Vargas-Caballero laboratories have collaborated with Dr Sandrine Willaime-Morawaek to characterize a 3D neural model of iPSCs derived from AD patients with a FAD mutation (L286V) that causes an early-onset form of AD, and aged matched controls. The Human iPSC-Derived Neural Stem Cells (hiPSC-NSCs) (Axol Bioscience, ax0112) were combined with the MatrigelTM in order to create brain tissue in closed 3D, pathophysiology stimulating environment.
The hiPSCs-NSCs were cultured for 18 weeks and then immunohistochemistry (IHC) was performed using antibodies, GFAP, NeuN and MAP2. The IHC staining showed a population of astrocytes and mature cortical neurons. The 4R tau isoform and electrophysiological readouts that signify neuronal maturity were identified in these populations. Additionally, in comparison to the controls, the patient-derived 3D cultures showed significant levels of tau hyperphosphorylation.
Initial observations indicate that the 3D scaffold provides a microenvironment that can reconstruct the pathophysiology alterations in the diseased neurons. This iPSC-derived model is a valuable translational platform for therapeutic drug screening processes due to the generation of AD-relevant proteins combined with the early trigger of tau pathology in the mature disease neurons.
- Korolev I.O. Alzheimer’s Disease: A Clinical and Basic Science Review . MSRJ, 2014. VOL: 04: p. 24-33.
- Alzheimer’s research UK: http://www.alzheimersresearchuk.org/about-dementia/facts-stats/
- Bertram L and Tanzi R.E. Genome-wide association studies in Alzheimer’s disease . Human Molecular Genetics, 2009, Vol. 18, Review Issue 2 R137–R145.
- De Felice F.G, Lourenco M.V and Ferreira S.T. How does brain insulin resistance develop in Alzheimer’s disease? Alzheimer’s & Dementia 10 (2014) S26–S32.
- Yagi T, Ito D, Okada Y et al. Modelling familial Alzheimer's disease with induced pluripotent stem cells . Hum Mol Genet. 2011 Dec 1; 20(23):4530-9.
- Israel M.A, Yuan S.H, Bardy C, Reyna S.M, Mu Y et al. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells . Nature. 2012 Jan 25; 482(7384):216-20.
About AXOL Biosciences
Axol specializes in human cell culture.
Axol produces high quality human cell products and critical reagents such as media and growth supplements. We have a passion for great science, delivering epic support and innovating future products to help our customers advance faster in their research.
Our expertise includes reprogramming cells to iPSCs and then differentiating to various cell types. We supply differentiated cells derived from healthy donors and patients of specific disease backgrounds. As a service, we also take cells provided by customers (primary or iPSC) and then do the reprogramming (when necessary) and differentiation. Clearly, by offloading the burden of generating cells, your time is freed up to focus on the research. Axol holds the necessary licenses that are required to do iPSC work.
The package wouldn't be complete without optimized media, coating solutions and other reagents. Our in-house R&D team works hard to improve on existing media and reagents as well as innovate new products for human cell culture. We also supply a growing range of human primary cells; making Axol your first port of call for your human cell culture needs.
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