Reversible age impairments in neurite outgrowth by manipulations of astrocytic GFAP.
Aging is associated with neuron atrophy and impaired sprouting after lesions. In contrast during normal aging without neurodegenerative diseases, astrocytes display increasing activation, with progressive increases of glial fibrillary acidic protein (GFAP) beginning before midlife. Because many neuronal functions depend on astrocytic support, we developed a heterochronic co-culture system to study influences of aging astrocytes on neurons. Neurite outgrowth by embryonic neurons (E18) was markedly less when co-cultured with confluent astrocytes derived from old (24 mo) versus young (3 mo) cortex. These impairments were reversible. Diminishing the GFAP levels of old astrocytes by RNAi restored neurite outgrowth, whereas overexpression of GFAP in young astrocytes modeled these effects of aging by reducing neurite outgrowth. Quantitative relationships were found such that neurites were co-localized with high intensity laminin, which both varied inversely with GFAP. These results implicate increased astrocytic GFAP expression as a proximal cause of neuron atrophy during normal aging.
Rozovsky
Irina
I
Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, 3715 McClintock Ave., Los Angeles, CA 90089-0191, USA. rozovsky@molbio.usc.edu
Wei
Min
M
Morgan
Todd E
TE
Finch
Caleb E
CE
D000367:Age Factors; D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques / Q000379:methods; D018076:DNA, Complementary / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods; D004622:Embryo, Mammalian; D004958:Estradiol / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D007797:Laminin / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014947:Wounds and Injuries / Q000378:metabolism
D018076:DNA, Complementary; D005904:Glial Fibrillary Acidic Protein; D007797:Laminin; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C085284:microtubule-associated protein 1B; D004958:Estradiol