The lack of accumulation of senile plaques or amyloid burden in Alzheimer's disease suggests a dynamic balance between amyloid deposition and resolution.

A beta, a nearly insoluble peptide, is generally assumed to irreversibly deposit and accumulate as senile plaques (SP) during the course of Alzheimer's disease (AD). We have studied temporal neocortex of normal elderly subjects, AD patients, and elderly Down syndrome (DS) patients to determine whether A beta accumulates with age or with increasing duration of illness. We measured the number, size distribution, and total area (amyloid burden) of A beta immunoreactive deposits using computerized image analysis techniques. We found far fewer SP in normal control subjects than in AD patients, who in turn have fewer SP than elderly DS patients. No measure of A beta correlated with age in the control subjects, nor duration of illness in AD or DS patients. These data indicate that A beta may not continue to accumulate during these disease processes and support the view that the amount of A beta observed at autopsy may reflect competing processes of deposition and resolution of amyloid.

Kunitz protease inhibitor-containing amyloid beta protein precursor immunoreactivity in Alzheimer's disease.

The amyloid beta protein (beta/A4) that is deposited in senile plaques and in cerebral vessels in Alzheimer's disease (AD) is derived from a larger membrane-associated glycoprotein, the amyloid beta protein precursor (APP). The gene encoding APP produces at least four major transcripts. Three of the four transcripts contain an alternatively-spliced exon encoding a Kunitz protease inhibitor domain (KPI). We now report the results of a series of experiments using novel immunohistochemical reagents to anatomically localize beta/A4, APP, and KPI-containing forms of APP (APP-KPI) in the hippocampal formation and temporal neocortex. A new monoclonal antibody against beta/A4 recognized senile plaques and vascular amyloid, but no cellular elements. Anti-APP and anti-KPI monoclonal antibodies stained neurons, including proximal axons and dendrites. The neuritic component of some plaques in patients with AD and in elderly control individuals were also immunoreactive for both APP and APP-KPI. Quantitative assessment of senile plaques in temporal neocortex showed that, on average, about one-third of beta/A4 immunoreactive plaques stained with either anti-APP or anti-KPI. Amyloid beta protein precursor and APP-KPI immunoreactivity were also found in the white and grey matter vessels of both AD patients and control individuals. These results suggest that KPI-containing forms of APP are present in dystrophic neurites of senile plaques, and normally in neurons, neuronal processes, and in the vascular compartment in the brain. Thus, APP-KPI is in a position to be intimately associated with beta/A4 deposition in the neuropil, in plaques and in amyloid angiopathy.

Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease.

We studied the topographic distribution of Alzheimer's disease (AD)-type pathologic changes in the brains of 25 presumed nondemented elderly individuals. Neurofibrillary tangles (NFT) and senile plaques (SP) were evaluated quantitatively in nine to 20 cytoarchitectural fields using thioflavine S, Alz-50, and anti-beta/A4 amyloid immunohistochemistry. Our observations suggest that (1) most individuals over the age of 55 have at least a few NFT and SP; (2) the topographic distribution of NFT and SP in nondemented elderly individuals follows a consistent pattern of vulnerability in different cytoarchitectural areas; (3) NFT occur most frequently in the entorhinal and perirhinal cortices and the CA1/subiculum field of the hippocampus, while neocortical areas are less frequently affected; (4) immunohistochemically defined subtypes of SP have distinct patterns of distribution. beta/A4 immunoreactive SP are present in neocortical areas much greater than limbic areas. Alz-50 immunoreactive SP are infrequent and limited to those areas that contain Alz-50-positive neurons and NFT. These patterns closely match the hierarchical topographic distribution of NFT and SP observed in AD, suggesting a commonality in the pathologic processes that lead to NFT and SP in both aging and AD.

The pattern of NADPH-diaphorase staining, a marker of nitric oxide synthase activity, is altered in the perforant pathway terminal zone in Alzheimer's disease.

NADPH-diaphorase positive neurons are relatively spared in Alzheimer's disease (AD). We show here, however, that the pattern of NADPH-diaphorase staining in the neuropil of the hippocampus changes dramatically in the brains of patients with AD. Control individuals displayed a striking band of NADPH-diaphorase staining in the middle 1/3 of the molecular layer of the dentate gyrus; this band was absent in AD. Staining in the molecular layer was reduced 18-31% in AD (P < 0.001) with the greatest loss in the most severely affected cases. NADPH diaphorase is thought to reflect the presence of nitric oxide synthase. Because nitric oxide has been implicated in long-term potentiation, changes in its expression could reflect loss of synapses important for memory formation.

Relative sparing of nitric oxide synthase-containing neurons in the hippocampal formation in Alzheimer's disease.

Nitric oxide (NO) is an endogenous neuromodulator that may mediate neurotoxic effects of glutamate. NO-synthesizing neurons are, however, resistant to NO- and glutamate-induced neurotoxicity. We now show that NO synthase neurons are selectively spared in patients with Alzheimer's disease, even in a severely affected region of the brain such as the hippocampal formation.