Abstract
beta-amyloid (Abeta) is presumed to play a pathogenic role in Alzheimer's disease (AD). However, there is an imperfect correlation between Abeta deposition and neuronal loss or dementia. To clarify neuronal responses to Abeta, Abeta-induced gene expression in cultured cortical neurons was analyzed by differential display followed by Northern blotting. Here we report that nonaggregated or aggregated Abeta induced microtubule-associated protein 1B (MAP1B) mRNA, especially the alternative transcript containing exon 3U, before disruption of the cell membrane by Abeta. An alternative transcript containing exon 3U is translated into an N-terminal truncated shorter isoform of MAP1B. Transfection experiments reveal that overexpression of this isoform does not accelerate neurite outgrowth or apoptosis of cortical neurons. In contrast, overexpression of MAP1B fragments containing the N-terminal 126 amino acids promoted neurite outgrowth and neuronal apoptosis. These results suggest that Abeta does not induce deleterious full-length MAP1B directly, but overexpression of full-length MAP1B might act as an effector of cell death in neurodegenerative disorders related to cytoskeletal abnormalities.
Highlights
The accumulation of -amyloid (A)1 plaques and neurofibrillary tangles and neuronal loss in the neocortex are hallmarks of Alzheimer’s disease (AD)
Overexpression of microtubule-associated protein 1B (MAP1B) fragments containing the N-terminal 126 amino acids promoted neurite outgrowth and neuronal apoptosis. These results suggest that A does not induce deleterious fulllength MAP1B directly, but overexpression of fulllength MAP1B might act as an effector of cell death in neurodegenerative disorders related to cytoskeletal abnormalities
MAP1B Was Induced by Either Nonaggregated or Aggregated A-(1– 42) Treatment before Neuronal Death—To identify Aresponsive genes by differential display RT-PCR before the disruption of the cell membrane by A, we compared RNA fingerprinting patterns from neurons exposed to A-(1– 42) (5 M) for 3 h with those from control neurons
Summary
A, -amyloid; AD, Alzheimer’s disease; MAP1B, microtubule associated protein 1B; APP, amyloid precursor protein; MEM, minimum essential medium; DIV, days in vitro; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; RT, reverse transcriptase. Protein (APP) with V171F or K670N/M671L develop A plaques in the neocortex progressively with age [8, 9] but do not show neuronal loss in the neocortex [10, 11]. These contradictory findings in vitro and in vivo suggest that A induces molecules that activate the cell death pathway and molecules that protect neurons from A toxicity in the neocortex. The results presented here demonstrate that nonaggregated or aggregated A induces MAP1B mRNA, especially the alternative transcript containing exon 3U. Transfection experiments of MAP1B isoforms in cultured cortical neurons indicated that full-length MAP1B but not the alternative MAP1B isoform resulted in the acceleration of neuronal death
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