Tampellini D, Rahman N, Lin MT, Capetillo-Zarate E, Gouras GK.
Impaired β-amyloid secretion in Alzheimer's disease pathogenesis.
J Neurosci. 2011 Oct 26;31(43):15384-90.
PubMed.
These are two very interesting papers discussing the production of Aβ with age. Soyon Hong and Dennis Selkoe's work in awake, behaving mice is particularly interesting as it elegantly shows that dense plaques are in equilibrium with soluble Aβ in the parenchyma, both sequestering exogenously added Aβ and acting as a source of Aβ when γ-secretase is inhibited. This supports the body of evidence showing that plaques are toxic to the nearby neurites and synapses because they are a local source of soluble Aβ species.
Aside from findings related to the intraneuronal accumulation of Aβ in the Alzheimer’s disease (AD) brain, this interesting and important paper from the Gouras lab brings to the forefront a neglected, but critical, issue in AD research: that of the age of the neurons that are investigated in cell culture. Most studies are done with embryonic or neonatal neurons, although the processes related to the aging brain and age-related diseases, such as AD, occur in very old neurons that may be very different from the embryonic ones. For example, the intracellular accumulation of oligomeric Aβ found at old age in some mouse models of AD (1), and in the human brain (2), is quite infrequent in primary neurons from embryonic mouse brains. The neurons in the old brain have gone through a history that marked them in very specific ways, and this history cannot be reproduced in culture, especially if these neurons are used without allowing them to age. The Gouras study allows for such aging, and this aging in the culture dish enabled the observations communicated in this study. Although the months-long aging required to generate the typical pathological lesions (e.g., plaques) in the brains of mouse models of AD differs from the weeks-long (at best) aging of neurons in culture, such experimental aging can be a good in-vitro model for studying the incipient stages of the disease process, as this study nicely shows.
Experts in the biology of cultured neurons, such as Gary Banker, consider that the embryonic neurons mature pretty well, so they eventually could correspond to cells from a two- to three-week-old animal. Also, these cultured neurons might respond to environmental challenges similarly to an adult neuron, and they should be subjected to such stress whenever possible. Culturing neurons derived from the adult brain—which would be ideal—appears to pose insurmountable problems. Reprogramming cells with iPS technology, or direct conversion of adult skin fibroblasts into neurons in culture (3)—as now is becoming the norm—has its own problems. The “history” of cells converted into neurons is not that of a neuron; also, do they remember this history? Researchers will continue to use neurons obtained from the embryonic or neonate brain. However, to be more relevant to diseases of the old age, these neurons should be allowed to age in culture for extended periods of time, as the Gouras lab did.
We also think that, in some cases, neuronal cell lines could provide insights into the biology of the aging neuron (see, e.g., 4). Although some researchers dislike this idea—often for good reasons—such cells can live in culture for quite a long time until senescence kicks in. But could a senescent neuronal cell not tell us something about neurons in the aging brain?
References:
Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM.
Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice.
Neuron. 2005 Mar 3;45(5):675-88.
PubMed.
Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield JP, Haroutunian V, Buxbaum JD, Xu H, Greengard P, Relkin NR.
Intraneuronal Abeta42 accumulation in human brain.
Am J Pathol. 2000 Jan;156(1):15-20.
PubMed.
Muresan Z, Muresan V.
Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells.
Mol Cell Biol. 2006 Jul;26(13):4982-97.
PubMed.
Comments
University of Edinburgh
These are two very interesting papers discussing the production of Aβ with age. Soyon Hong and Dennis Selkoe's work in awake, behaving mice is particularly interesting as it elegantly shows that dense plaques are in equilibrium with soluble Aβ in the parenchyma, both sequestering exogenously added Aβ and acting as a source of Aβ when γ-secretase is inhibited. This supports the body of evidence showing that plaques are toxic to the nearby neurites and synapses because they are a local source of soluble Aβ species.
View all comments by Tara Spires-JonesRutgers - New Jersey Medical School
Aside from findings related to the intraneuronal accumulation of Aβ in the Alzheimer’s disease (AD) brain, this interesting and important paper from the Gouras lab brings to the forefront a neglected, but critical, issue in AD research: that of the age of the neurons that are investigated in cell culture. Most studies are done with embryonic or neonatal neurons, although the processes related to the aging brain and age-related diseases, such as AD, occur in very old neurons that may be very different from the embryonic ones. For example, the intracellular accumulation of oligomeric Aβ found at old age in some mouse models of AD (1), and in the human brain (2), is quite infrequent in primary neurons from embryonic mouse brains. The neurons in the old brain have gone through a history that marked them in very specific ways, and this history cannot be reproduced in culture, especially if these neurons are used without allowing them to age. The Gouras study allows for such aging, and this aging in the culture dish enabled the observations communicated in this study. Although the months-long aging required to generate the typical pathological lesions (e.g., plaques) in the brains of mouse models of AD differs from the weeks-long (at best) aging of neurons in culture, such experimental aging can be a good in-vitro model for studying the incipient stages of the disease process, as this study nicely shows.
Experts in the biology of cultured neurons, such as Gary Banker, consider that the embryonic neurons mature pretty well, so they eventually could correspond to cells from a two- to three-week-old animal. Also, these cultured neurons might respond to environmental challenges similarly to an adult neuron, and they should be subjected to such stress whenever possible. Culturing neurons derived from the adult brain—which would be ideal—appears to pose insurmountable problems. Reprogramming cells with iPS technology, or direct conversion of adult skin fibroblasts into neurons in culture (3)—as now is becoming the norm—has its own problems. The “history” of cells converted into neurons is not that of a neuron; also, do they remember this history? Researchers will continue to use neurons obtained from the embryonic or neonate brain. However, to be more relevant to diseases of the old age, these neurons should be allowed to age in culture for extended periods of time, as the Gouras lab did.
We also think that, in some cases, neuronal cell lines could provide insights into the biology of the aging neuron (see, e.g., 4). Although some researchers dislike this idea—often for good reasons—such cells can live in culture for quite a long time until senescence kicks in. But could a senescent neuronal cell not tell us something about neurons in the aging brain?
References:
Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron. 2005 Mar 3;45(5):675-88. PubMed.
Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield JP, Haroutunian V, Buxbaum JD, Xu H, Greengard P, Relkin NR. Intraneuronal Abeta42 accumulation in human brain. Am J Pathol. 2000 Jan;156(1):15-20. PubMed.
Qiang L, Fujita R, Yamashita T, Angulo S, Rhinn H, Rhee D, Doege C, Chau L, Aubry L, Vanti WB, Moreno H, Abeliovich A. Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons. Cell. 2011 Aug 5;146(3):359-71. PubMed. RETRACTED
Muresan Z, Muresan V. Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells. Mol Cell Biol. 2006 Jul;26(13):4982-97. PubMed.
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