The 39- to 43-amino acid amyloid beta protein (beta AP), which is deposited as amyloid in Alzheimer's disease, is encoded as an internal peptide that begins 99 residues from the carboxyl terminus of a 695- to 770-amino acid glycoprotein referred to as the amyloid beta protein precursor (beta APP). To clarify the processing that produces amyloid, carboxyl-terminal derivatives of the beta APP were analyzed. This analysis showed that the beta APP is normally processed into a complex set of 8- to 12-kilodalton carboxyl-terminal derivatives. The two largest derivatives in human brain have the entire beta AP at or near their amino terminus and are likely to be intermediates in the pathway leading to amyloid deposition.

Senile plaques are polymorphous P-amyloid protein deposits found in the brain in Alzheimer disease and normal aging. This .3-amyloid protein is derived from a larger precursor molecule of which neurons are the principal producers in brain. We found that amyloid precursor protein (APP)-immunoreactive neurites were involved in senile plaques and that only a subset of these neurites showed markers for the abnormal filaments characteristic ofneurofibrillary pathology. In the neocortex of nondemented individuals with senile plaques but spared of neurofibrillary pathology, dystrophic neurites in senile plaques showed only APP accumulation. In contrast, in the brains of Alzheimer patients, virtually all APP-immunoreactive neurites also showed immunoreactivity with ubiquitin, x, and phosphorylated neurofilaments. The presence of X and neurofrlament epitopes in dystrophic neurites in senile plaques was correlated with the extent of neurofibrillary pathology in the surrounding brain tissue. Accumulation of APP and the formation of neurofibrillary pathology in senile plaque neurites are therefore distinct phenomena. Our findings suggest that APP accumulation in senile plaque neurites occurs prior to X accumulation and is therefore more closely related to appearance of neuritic dystrophy.Senile plaques (SP) are extracellular amyloid deposits found in the brain most prominently in Alzheimer disease (AD) but also in normal aging (1). Their 6-to 10-nm-wide filaments consist of a 39-to 42-amino acid f3-amyloid protein (f3-AP) (2), which is derived from a much larger transmembrane amyloid precursor protein (APP) (3-5). The morphology and size of SP are highly variable and are regionally dependent (6). Recent studies have addressed the pathogenetic role of neurons, astrocytes, microglia, and capillaries in the development of SP (7-11). Another prominent lesion of AD is the accumulation of straight and paired helical filaments in neuronal cell bodies and in neurites (12). Studies of Down syndrome patients, who invariably develop pathology like that in AD, have shown that amyloid is probably deposited before any neurofibrillary pathology occurs (13). The most frequent form of dystrophic neurites in AD are neuropil threads that are not confined to the SP (14). Furthermore, neuropil threads are also found in progressive supranuclear palsy (15) and subacute sclerosing panencephalitis (16) APP has been localized to cell processes that were tentatively identified as neurites in AD brains (20-23). We reported previously that APP-positive cell processes occur in the absence of M-AP deposits, in diffuse SP, as well as in fully developed f3-AP core-containing plaques (24). These findings suggested that APP accumulation in cell processes could contribute to the deposition of f3-AP in SP.The present study was undertaken to define the cellular origin of APP-immunostained cell processes in SP and to define their relationship to neurofibrillary pathology in AD and normal aging. MATERIAL AND METHODSWe studied the hippocampus and the temp...

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Both neural and nonneural human tissues from patients with or without Alzheimer's disease (AD) were surveyed to detect the presence of the beta-amyloid protein and its precursors. This was accomplished using polyclonal and monoclonal antibodies to epitopes in the 695 amino acid long beta-APP (i.e., beta-APP695), as well as in related beta-APPs. Immunoreactivity in beta-APP in brain was prominent in senile plaques, extraneuronal tangles, and neurons. Outside the brain, beta-APP staining was seen in neurons and satellite glial cells of the dorsal root, enteric and trigeminal ganglia, the adeno- and neurohypophysis, megakaryocytes, and adrenal gland in samples from patients with AD and those without AD. Western blots of neocortex revealed three major proteins with apparent molecular masses of 105, 115, and 125 kDa in the insoluble membrane-associated fractions, while two broad bands with a molecular weight centered at about 100 and 120 kDa were detected in soluble fractions. In addition, the pituitary and adrenal glands as well as cardiac muscle revealed prominent immunobands in membrane-associated fractions. Notably, other nonneural tissues were devoid of beta-APP immunoreactivity. Thus, the beta-APPs are detectable only in a limited number of nonneural tissues. Taken together, these data suggest that beta-APPs produced in the brain are sources of beta-APP peptides that accumulate as senile plaques in AD.