Monoclonal antibody identification of subpopulations of cerebral cortical neurons affected in Alzheimer disease.

Abstract

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 neuroframent 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.Alzheimer disease (AD) is a dementing degenerative disease of the central nervous system (CNS) of unknown cause. Neuronal loss, neurofibrillary tangles, neuritic plaques, amyloid angiopathy, and, less commonly, granulovacuolar degeneration and Hirano bodies constitute the major histopathology.Whereas much attention has been focused on the neurofibrillary pathology, neuronal loss has been more difficult to evaluate. There are relatively few selective histologic or molecular markers for human neuronal subpopulations, thus limiting identification of the vulnerable neurons. Enzymes important in the biosynthesis of neurotransmitters, such as acetylcholine in the nucleus basalis of Meynert (1) and norepinephrine in the locus ceruleus (2), have been useful correlates in the histochemical analyses of subcortical nuclei in normal and AD tissue. Neuronal loss within the cerebral cortex also may be highly selective. Neuritic plaques and neurofibrillary tangles have been quantified according to their regional distribution and correlated with neuronal loss within the hippocampus and limbic system and in neocortical association areas (3). Phosphorylated and nonphosphorylated neurofilament protein (4, 5), the microtubule-associated proteins tau (6) and microtubule...

A novel member to the family of perineuronal antigens associated with subpopulatios of central neurons in the rat

“…But the intensity of the staining was relatively constant along the entire perimeter of a particular cell. These patterns of immunostaining resemble those exhibited by MAbs 473, 376, and 1B5 in the monkey neocortex, Cat-301 , VC 1.t, and VC 5.1 (Arimatsu et al 1987) in the cat neocortex, Tor 23 (Kushner 1984) in the rat neocortex, 4F4 (Yamamoto et al 1988) in the mouse neocortex, and 6A2 (Miller et al 1987) in the human neocortex.…”

“…MAb 374 is clearly different from Cat 301, 353 because the latter stains only hippocampal cells in the rat cerebral cortex (Hendry et al 1988 (Yamamoto et al 1988) and 6A2 (Miller et al 1987) are not described in the rat, so that they cannot be compared with MAb 374. MAb 374 appears to be a novel member of a family of MAbs giving pericellular staining of small subsets of central neurons.…”

“…In recent years a number of groups reported a peculiar class of MAbs that stain the perimeters of small subsets of central neurons: Cat-301 (McKay and Hockfield 1982;Hendry et al 1988), VCI.1 and VC5.1 (Arimatsu et al 1987;Naegele et al 1988), Tor 23 (Kushner 1984;Stephenson and Kushner 1988), 4F4 (Yamamoto et al Offprint requests to: S.C. Fujita 1988), and 6A2 (Miller et al 1987;Hinton et al 1988). We also obtained a set of such antibodies and described MAb 473 (Watanabe et al 1989), and MAbs 528 and 376 .…”

Carbonyl‐Related Posttranslational Modification of Neurofilament Protein in the Neurofibrillary Pathology of Alzheimer's Disease

“…The monoclonal antibody 3A4 was generated as previously described (Fujita et al ., 1982), and initial immunocytochemical analyses were documented (Miller et al ., 1987 ;Hinton et al ., 1988) .…”

Gene expression and mental disease

“…Finally, the amyloid protein is being mapped in the brain using monoclonal antibodies directed against various parts of the molecule, and identified in discrete cell populations (Majocha et al 1988). These can then be related to neuronal groups defined by other parameters such as connectivity (Pearson et al 1985), transmitter type (Bowen, 1988) or antigenic properties (Miller et al 1987). …”