Kunitz Protease Inhibitor-Containing Amyloid β Protein Precursor Immunoreactivity in Alzheimer's Disease

Abstract

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.

Jun NH2-terminal Kinase (JNK) Interacting Protein 1 (JIP1) Binds the Cytoplasmic Domain of the Alzheimer's β-Amyloid Precursor Protein (APP)

“…The now free JIP1 would be able to scaffold and cause activation of the JNK signaling pathway as it does in response to anoxic and excitotoxic stress. This may result in dystrophic changes to neurites (80) and neuronal apoptosis.…”

Neuronal expression of myeloperoxidase is increased in Alzheimer's disease

“…For double staining experiments, we used double immunofluorescence confocal microscopy with bodipy-fluorescein (Molecular Probes, Eugene, OR, USA) and Cy-3 (Jackson Immuno-Research, West Grove, PA, USA) to visualize myeloperoxidase and b-amyloid deposits (monoclonal antibody 10D5; Hyman et al 1992), paired helical filaments (monoclonal antibody PHF-1; Greenberg et al 1992), microglia (monoclonal antibody LN-3, ICN) or neurofilaments (monoclonal antibody SMI-32, Sternberger Monoclonals, Lutherville, MD, USA). Confocal microscopy was carried out with a Bio-Rad 1024 instrument using a kyrpton-argon laser and a Leica Aristophot microscope.…”

Treatment with an Amyloid-β Antibody Ameliorates Plaque Load, Learning Deficits, and Hippocampal Long-Term Potentiation in a Mouse Model of Alzheimer's Disease

“…To help determine whether A␤ deposition was responsible for any cognitive deficits in the old PDAPP mice, another group of 17-to 19-month-old PDAPP mice was tested in the water maze after treatment with the anti-A␤ antibody 10D5, a mouse monoclonal antibody that binds to A␤ amino acids 3-6 (Hyman et al, 1992;Bacskai et al, 2002) and is specific for human A␤. PDAPP mice were given weekly intraperitoneal injections of 0.5 mg of 10D5 or saline (volume, 0.2 ml), and WT littermates were given saline injections.…”