Editors' ChoiceAlzheimer’s Disease

The Benefits of Culture

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Science Translational Medicine  15 Feb 2012:
Vol. 4, Issue 121, pp. 121ec28
DOI: 10.1126/scitranslmed.3003775

It can take decades for the devastating symptoms of neurodegenerative disorders like Alzheimer’s disease (AD) to emerge, which has proved a big challenge for researchers trying to mimic development and progression of these diseases in cultured neurons or in mice. Most patients with AD have a sporadic form of the disease of unknown etiology, with the pathological events culminating in memory loss and dementia taking decades to unfold. However, a small number of patients with the so-called familial form of AD as well as individuals with Down syndrome develop the pathological hallmarks of AD much sooner, with symptoms emerging in middle age or even the teen years in Down syndrome. In a new study in Nature, Israel et al. combine the latest stem cell technology to make neurons from AD patients and demonstrate that these cultured neurons develop AD pathology rapidly. In a related Rapid Publication in Science Translational Medicine, Shi et al. present similar data for cultured cortical neurons derived from Down syndrome patients. These two studies demonstrate that the decades-long process of AD pathogenesis can be recreated in a culture dish in a few months, providing a way to analyze in detail the aberrant cellular events that lead to the demise of neurons in AD.

In their new study, Israel et al. first made induced pluripotent stem cells from fibroblasts taken from two patients with familial AD, two patients with the sporadic form of AD, and two individuals of a similar age who did not show signs of dementia. The researchers then coaxed the induced pluripotent stem cells to become neural progenitor cells, which they then plied with specific factors to make them form neurons. Using flow cytometry, they obtained cell populations comprising more than 90% neurons. The neurons behaved normally, expressing AMPA and GABA receptors, forming functional synapses and firing action potentials. The authors wondered whether the cultured neurons derived from AD patients would show any indications of AD pathology. They discovered that neurons from the two familial AD patients and from one patient with sporadic AD showed higher concentrations of amyloid-β peptide 40 and hyperphosphorylated tau protein than did neurons from healthy age-matched individuals and the second sporadic AD patient. Overproduction of amyloid-β peptides due to misprocessing of amyloid precursor protein and formation of neurofibrillary tangles due to aberrant hyperphosphorylation of tau are hallmarks of AD pathogenesis in the human brain. Could this pathological process be interrupted with the drugs that inhibit the β-secretase and γ-secretase proteases and prevent misprocessing of amyloid precursor protein? The authors show that neurons derived from the two familial and one sporadic AD patient and treated with the β-secretase inhibitor exhibited a decrease in hyperphosphorylated tau. This suggests somewhat surprisingly that preventing misprocessing of amyloid precursor protein somehow decreases aberrant hyperphosphorylation of tau, thus connecting these two apparently separate pathogenic events. The new work shows that cultured neurons generated from induced pluripotent stem cells derived from patients with familial AD or some forms of sporadic AD can provide fresh insights into the pathogenic events that cause this disease. These cultured neurons also provide a quick way to test new candidate drugs and thus may help to speed up discovery of new therapies to slow AD’s relentless progress.

M. A. Israel et al., Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216–220 (2012). [Abstract]

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