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Monoclonal Antibody Identification of Subpopulations of Cerebral Cortical Neurons Affected in Alzheimer disease

Miller, Carol A. and Rudnicka, Maria and Hinton, David R. and Blanks, Janet C. and Kozlowski, Mark (1987) Monoclonal Antibody Identification of Subpopulations of Cerebral Cortical Neurons Affected in Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America, 84 (23). pp. 8657-8661. ISSN 0027-8424. PMCID PMC299605. doi:10.1073/pnas.84.23.8657.

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Neuronal degeneration is one of the hallmarks of Alzheimer disease (AD). Given the paucity of molecular markers available for the identification of neuronal subtypes, the specificity of neuronal loss within the cerebral cortex has been difficult to evaluate. With a panel of four monoclonal antibodies (mAbs) applied to central nervous system tissues from AD patients, we have immunocytochemically identified a population of vulnerable cortical neurons; a subpopulation of pyramidal neurons is recognized by mAbs 3F12 and 44.1 in the hippocampus and neocortex, and clusters of multipolar neurons in the entorhinal cortex reactive with mAb 44.1 show selective degeneration. Closely adjacent stellate-like neurons in these regions, identified by mAb 6A2, show striking preservation in AD. The neurons recognized by mAbs 3F12 and 44.1, to the best of our knowledge, do not comprise a single known neurotransmitter system. mAb 3A4 identifies a phosphorylated antigen that is undetectable in normal brain but accumulates early in the course of AD in somas of vulnerable neurons. Antigen 3A4 is distinct from material reactive with thioflavin S or antibody generated against paired helical filaments. Initially, antigen 3A4 is localized to neurons in the entorhinal cortex and subiculum, later in the association neocortex, and, ultimately in cases of long duration, in primary sensory cortical regions. mAb 3F12 recognizes multiple bands on immunoblots of homogenates of normal and Ad cortical tissues, whereas mAb 3A4 does not bind to immunoblots containing neurofilament proteins or brain homogenates from AD patients. Ultrastructurally, antigen 3A4 is localized to paired-helical filaments. Using these mAbs, further molecular characterization of the affected cortical neurons is now possible.

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Additional Information:© 1987 by the National Academy of Sciences Communicated by Seymour Benzer, August 17, 1987 Three of the four mAbs used (3F12, 3A4, 6A2) were generously provided by Dr. Seymour Benzer. Other antibodies were generously provided by Drs. L. Gerace (anti-lamin), K. Iqbal and I. Iqbal (anti-paired helical filament), M. Kirschner and G. Perry (anti-tau), and P. Davies (Alz-50). The authors are grateful for helpful discussions with Drs. J. Garner, D. Teplow, V. Henderson, and M. Halekis; for secretarial assistance of C. Elkins and P. Mora; and for technical assistance of M. Anderson, C. Williams, and C. Spee. This project was supported in part by Grant 1-P50-AG 05142 from the National Institute for Aging to C.A.M., Grant 2-RO1-EY03042-07 from the National Eye Institute to J.C.B., Research Career Development Award EY00188 to J.C.B., Grant EY03040 from the National Eye Institute (a Core Center grant to Doheny Eye Foundation), Grant 5-RO1-MH 39145 from the National Institute of Mental Health to C.A.M., a Parsons Foundation grant to C.A.M., a grant from the Hereditary Disease Foundation to C.A.M., a grant from the Medical Research Council of Canada to D.R.H., a grant from the Gordon Ross Foundation to D.R.H., a grant from the Margaret W. and Herbert Hoover, Jr., Foundation to J.C.B., and Grant NS-DSB-8409366 from the National Science Foundation to Seymour Benzer. Huntington disease CNS tissues were obtained from the National Neurological Research Bank, VAMC Wadsworth Division, Los Angeles, CA 90073, which is sponsored by National Institute of Neurological and Communicative Disorders and Stroke/National Institute of Mental Health, NMSS, HD Foundation, Comprehensive Epilepsy Program and Veterans Administration. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Funding AgencyGrant Number
NIH1-P50-AG 05142
NIH5-RO1-MH 39145
Ralph M. Parsons FoundationUNSPECIFIED
Hereditary Disease FoundationUNSPECIFIED
Medical Research Council of CanadaUNSPECIFIED
Gordon Ross Medical FoundationUNSPECIFIED
Margaret W. and Herbert Hoover, Jr. FoundationUNSPECIFIED
Subject Keywords:pyramidal neurons; neurofibrillary tangles; immunoblot; immunocytochemistry; disease progression
Issue or Number:23
PubMed Central ID:PMC299605
Record Number:CaltechAUTHORS:MILpnas87
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6441
Deposited By: Archive Administrator
Deposited On:09 Dec 2006
Last Modified:08 Nov 2021 20:34

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