C. G. Rasool

Sharing of Specific Antigens by Degenerating Neurons in Pick's Disease and Alzheimer's Disease

NEUROPATHOLOGICAL studies during the past 15 years have established that dementia of the Alzheimer type, or Alzheimers disease, is the most common cause of intellectual failure in the elderly, acc...

Alzheimer's disease: Immunoreactivity of neurofibrillary tangles with anti-neurofilament and anti-paired helical filament antibodies

The origin of the paired helical filaments (PHF) that accumulate in human neurons during aging and in Alzheimers disease and their relationship to normal neurofilaments remain unclear. The observation that a rabbit antiserum to highly enriched PHF fractions specifically labeled PHF in Alzheimer neurofibrillary tangles but showed no reaction with neurofilaments or other normal cytoskeletal proteins led us to compare this antiserum to two monoclonal antibodies, RT97 and BF10, previously found to cross-react with tangles and with the 210,000 and 155,000 mol. wt. neurofilament proteins, respectively. Both alpha-PHF serum and the neurofilament monoclonals strongly immunolabel almost all neurofibrillary tangles in Alzheimer cortical sections. Double-immunolabeling studies show that both reagents recognize the same tangles and usually show identical patterns of staining of intraneuronal fibrous material. Following prolonged extraction of cortex in sodium dodecyl sulfate, a step which removes normal neurofilaments but leaves PHF intact, almost all isolated tangles retain strong immunoreactivity with alpha-PHF serum at an intensity which is slightly reduced from that in cortical sections. In contrast, only a small number of isolated tangles are stained strongly by RT97 and BF10; most show much decreased or no reactivity with these monoclonal neurofilament antibodies. This differential immunoreactivity was confirmed by double-labeling studies. Tangles prepared under gentle extraction conditions show strong reactivity with alpha-PHF antibodies but again only a small number are strongly labeled by RT97 and BF10. We conclude that neurofibrillary tangles in Alzheimers disease are heterogeneous as regards their filamentous content and contain both antigens cross-reacting with neurofilaments and antigens which are apparently unique to PHF and not shared with normal neurofilaments.

Alzheimer's disease: exposure of neurofilament immunoreactivity in SDS-insoluble paired helical filaments

In Alzheimers disease, neurofibrillary tangles (NFT) react with both antibodies to paired helical filaments (PHF) and certain antibodies to neurofilaments, for example, monoclonal RT97 against the 200,000 mol. wt. neurofilament protein. After isolating NFT by extraction in sodium dodecyl sulfate (SDS), PHF antibodies remain reactive while RT97 weakly stains only a minority of the extracted tangles. We now show that isolated NFT initially unreactive with RT97 apparently develop exposed antigenic sites following incubation under denaturing conditions. Our results suggest that at least one neurofilament epitope is buried in the SDS-insoluble PHF fiber and that conformational changes in PHF proteins allow its exposures.

Molecular Properties of Paired Helical Filaments and Senile Plaque Amyloid Fibers in Alzheimer’s Disease

In a disorder as complex and enigmatic as Alzheimer’s disease, numerous distinct research strategies must be applied simultaneously. While some experimental approaches will provide information about secondary events in the disease process, it is hoped that other strategies will yield clues to the fundamental biological process that initiates the neuronal degeneration. Most current investigations of the biological aspects of Alzheimer’s disease address one or more of three broad questions. The first question regards the etiologic event(s) that initiate the progressive loss of selected brain neurons. Research strategies in this area include molecular genetic investigations of the chromosomal locus and identity of an abnormal gene in hereditary forms of Alzheimer’s disease; the search for an infectious pathogen; and the study of the role of environmental toxins in this disease. The second broad question concerns the molecular mechanism of cell death, once the initiating event(s) have taken place, whether they are genetic, infectious and/or toxic. The third question is that of the identity of the degenerating neurons as to location, functional class and neurotransmitter status. This latter question in Alzheimer’s disease has received the most experimental attention during the past decade since it appears to offer the earliest chance of developing a therapy that could ameliorate symptoms of the disease. With the rapid development of molecular genetics and neuro-virology in recent years, experiments aimed at the first question are also accelerating.