TY - JOUR
T1 - Subventricular zone neural progenitors from rapid brain autopsies of elderly subjects with and without neurodegenerative disease
AU - Leonard, Brian W.
AU - Mastroeni, Diego
AU - Grover, Andrew
AU - Liu, Qiang
AU - Yang, Kechun
AU - Gao, Ming
AU - Wu, Jie
AU - Pootrakul, David
AU - van den Berge, Simone A.
AU - Hol, Elly M.
AU - Rogers, Joseph
PY - 2009/7/20
Y1 - 2009/7/20
N2 - In mice and in young adult humans, the subventricular zone (SVZ) contains multipotent, dividing astrocytes, some of which, when cultured, produce neurospheres that differentiate into neurons and glia. It is unknown whether the SVZ of very old humans has this capacity. Here, we report that neural stem/progenitor cells can also be cultured from rapid autopsy samples of SVZ from elderly human subjects, including patients with age-related neurologic disorders. Histological sections of SVZ from these cases showed a glial fibrillary acidic protein (GFAP)-positive ribbon of astrocytes similar to the astrocyte ribbon in human periventricular white matter biopsies that is reported to be a rich source of neural progenitors. Cultures of the SVZ contained 1) neurospheres with a core of Musashi-1-, nestin-, and nucleostemin-immunopositive cells as well as more differentiated GFAP-positive astrocytes; 2) SMI-311-, MAP2a/b-, and β-tubulin(III)-positive neurons; and 3) galactocerebroside-positive oligodendrocytes. Neurospheres continued to generate differentiated progeny for months after primary culturing, in some cases nearly 2 years postinitial plating. Patch clamp studies of differentiated SVZ cells expressing neuron-specific antigens revealed voltage-dependent, tetrodotoxin-sensitive, inward Na+ currents and voltage-dependent, delayed, slowly inactivating K+ currents, electrophysiologic characteristics of neurons. A subpopulation of these cells also exhibited responses consistent with the kinetics and pharmacology of the h-current. However, although these cells displayed some aspects of neuronal function, they remained immature, insofar as they did not fire action potentials. These studies suggest that human neural progenitor activity may remain viable throughout much of the life span, even in the face of severe neurodegenerative disease.
AB - In mice and in young adult humans, the subventricular zone (SVZ) contains multipotent, dividing astrocytes, some of which, when cultured, produce neurospheres that differentiate into neurons and glia. It is unknown whether the SVZ of very old humans has this capacity. Here, we report that neural stem/progenitor cells can also be cultured from rapid autopsy samples of SVZ from elderly human subjects, including patients with age-related neurologic disorders. Histological sections of SVZ from these cases showed a glial fibrillary acidic protein (GFAP)-positive ribbon of astrocytes similar to the astrocyte ribbon in human periventricular white matter biopsies that is reported to be a rich source of neural progenitors. Cultures of the SVZ contained 1) neurospheres with a core of Musashi-1-, nestin-, and nucleostemin-immunopositive cells as well as more differentiated GFAP-positive astrocytes; 2) SMI-311-, MAP2a/b-, and β-tubulin(III)-positive neurons; and 3) galactocerebroside-positive oligodendrocytes. Neurospheres continued to generate differentiated progeny for months after primary culturing, in some cases nearly 2 years postinitial plating. Patch clamp studies of differentiated SVZ cells expressing neuron-specific antigens revealed voltage-dependent, tetrodotoxin-sensitive, inward Na+ currents and voltage-dependent, delayed, slowly inactivating K+ currents, electrophysiologic characteristics of neurons. A subpopulation of these cells also exhibited responses consistent with the kinetics and pharmacology of the h-current. However, although these cells displayed some aspects of neuronal function, they remained immature, insofar as they did not fire action potentials. These studies suggest that human neural progenitor activity may remain viable throughout much of the life span, even in the face of severe neurodegenerative disease.
KW - Alzheimer's disease
KW - Neural precursors
KW - Neural stem cells
KW - Neuronal differentiation
KW - Neurospheres
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U2 - 10.1002/cne.22040
DO - 10.1002/cne.22040
M3 - Article
C2 - 19425077
AN - SCOPUS:67650106862
SN - 0021-9967
VL - 515
SP - 269
EP - 294
JO - Journal of Comparative Neurology
JF - Journal of Comparative Neurology
IS - 3
ER -