Comparison of β-protein/A4 deposits and Alz-50-stained cytoskeletal changes in the hypothalamus and adjoining areas of Alzheimer’s disease patients: amorphic plaques and cytoskeletal changes occur independently

Alzheimer’s disease is characterized neuropathologically by senile plaques and cytoskeletal changes. It has been proposed that amorphic plaques would locally induce anterograde propagation of cytoskeletal changes in consecutive neurons followed by amorphic plaque deposition at their axonal terminals. The Alzheimer changes would spread in this way along neural pathways. To test the ‘primary amyloid anatomical cascade hypothesis’, Congo red staining, β-protein/A4 (Aβ) antiserum and Alz-50, which recognizes cytoskeletal changes, were applied to the hypothalamus and adjoining brain areas of five Alzheimer’s disease patients of 40–90 years of age and five age- and sex-matched controls. The results showed that (1) virtually all Aβ plaques in the hypothalamus were of the Congo red-negative amorphic type; (2) amorphic plaques and Alz-50-stained cytokeletal changes were observed not only in all Alzheimer’s disease patients but also in a non-demented, 90-year-old control subject; (3) the density of amorphic plaques in the hypothalamus was unrelated to the duration of the dementia; (4) the density of amorphic plaques was unrelated to that of Alz-50-stained cytoskeletal changes; (5) double-labeling with anti-Aβ and Alz-50 did not show an evident topical relationship between amorphic plaque deposition and the occurrence of cytoskeletal changes; and (6) the distribution of Aβ and Alz-50 staining in five brain areas, for which essential anatomical information is available, did not support the primary amyloid anatomical cascade hypothesis. Amorphic plaques and cytoskeletal changes rather occur independently. Received: 22 September 1997 / Revised, accepted: 9 January 1998     

A direct demonstration of the perforant pathway terminal zone in Alzheimer''s disease using the monoclonal antibody Alz-50

The perforant pathways links the entorhinal cortex with the hippocampal formation and provides this structure with its major cortical input. The cells of origin of the perforant pathway are destroyed in Alzheimer's disease (AD) and a marked depletion of glutamate, the putative neurotransmitter in its terminal zone, occurs. We report that the monoclonal antibody Alz-50 recognizes an antigen in the terminal zone of the perforant pathway in AD. This observation provides direct evidence for the involvement of the perforant pathway in AD, and demonstrates that Alz-50 can be used to study neural connectivity in AD brains.     

Identification of FcγRI, II and III on normal human brain ramified microglia and on microglia in senile plaques in Alzheimer's disease

Using monoclonal antibodies to the three known human leukocyte IgG receptors, FcγR, we examined the expression of FcγR in normal brains and in Alzheimer's disease. We found FcγRI, II and III immunoreactivity in senile plaques and on ramified microglia throughout the cortex and white matter of normal and Alzheimer's disease brains. FcγRI expression was independently confirmed by a murine isotype binding study. These findings suggest that intrinsic FcγR may play an important role in normal and disordered immune-related processes in the brain. The support the idea that microglia are brain macrophages.     

The subunits of α2-macroglobulin receptor/low density lipoprotein receptor-related protein, native and transformed α2-macroglobulin and interleukin 6 in Alzheimer's disease

To explore the role of α₂-macroglobulin receptor/low density lipoprotein receptor-related protein (α₂M-R/LRP) and its ligands in the pathogenesis of Alzheimer's disease (AD), antibodies were raised against its α- and β-subunits and their expression pattern in the CNS in AD and control cases was correlated with that of native and transformed α₂-macroglobulin (α₂M) and interleukin 6 (IL-6). The transmembranous β-subunit of α₂M-R/LRP and transformed α₂M were found in plaque cores in AD. Extramembranous α-subunit and native α₂M immunoreactivities were localized in activated plaque-associated astrocytes and extracellulary in plaques. IL-6 immunostaining was associated with neurofibrillary changes, and was also found extracellularly in the center of plaques and in microglial cells. Our finding that plaque cores contain a second transmembranous protein fragment, the β-subunit of α₂M-R/LRP, suggests ongoing membrane-protein degradation. By altering clearance and scavenger-like functions, fragmentation and breakdown of α₂M-R/LRP may have an important role in extracellular amyloid deposition and the formation of neurofibrillary tangles in AD.