Alzheimer's Disease-like Neuropathology Research Articles

Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology.

Transgenic PDAPP mice, which express a disease-linked isoform of the human amyloid precursor protein, exhibit CNS pathology that is similar to Alzheimer's disease. In an age-dependent fashion, the mice develop plaques containing beta-amyloid peptide (Abeta) and exhibit neuronal dystrophy and synaptic loss. It has been shown in previous studies that pathology can be prevented and even reversed by immunization of the mice with the Abeta peptide. Similar protection could be achieved by passive administration of some but not all monoclonal antibodies against Abeta. In the current studies we sought to define the optimal antibody response for reducing neuropathology. Immune sera with reactivity against different Abeta epitopes and monoclonal antibodies with different isotypes were examined for efficacy both ex vivo and in vivo. The studies showed that: (i) of the purified or elicited antibodies tested, only antibodies against the N-terminal regions of Abeta were able to invoke plaque clearance; (ii) plaque binding correlated with a clearance response and neuronal protection, whereas the ability of antibodies to capture soluble Abeta was not necessarily correlated with efficacy; (iii) the isotype of the antibody dramatically influenced the degree of plaque clearance and neuronal protection; (iv) high affinity of the antibody for Fc receptors on microglial cells seemed more important than high affinity for Abeta itself; and (v) complement activation was not required for plaque clearance. These results indicate that antibody Fc-mediated plaque clearance is a highly efficient and effective process for protection against neuropathology in an animal model of Alzheimer's disease.

Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4-10 and inhibit cytotoxicity and fibrillogenesis.

Immunization of transgenic mouse models of Alzheimer disease using amyloid-beta peptide (Abeta) reduces both the Alzheimer disease-like neuropathology and the spatial memory impairments of these mice. However, a therapeutic trial of immunization with Abeta42 in humans was discontinued because a few patients developed significant meningo-encephalitic cellular inflammatory reactions. Here we show that beneficial effects in mice arise from antibodies selectively directed against residues 4-10 of Abeta42, and that these antibodies inhibit both Abeta fibrillogenesis and cytotoxicity without eliciting an inflammatory response. These findings provide the basis for improved immunization antigens as well as attempts to design small-molecule mimics as alternative therapies.

Meta-analysis of postmortem studies of Alzheimer's disease-like neuropathology in schizophrenia.

To evaluate the hypothesis that patients with schizophrenia who have been treated with neuroleptics have a high rate of Alzheimer's disease-like neuropathology. Neuropathological studies indicating the presence or absence of Alzheimer's disease-like neuropathology in the postmortem brains of patients with schizophrenia, normal comparison subjects, and comparison subjects who had affective disorder were evaluated with Mantel-Haenszel chi-square and odds ratio analyses. Ten studies with relevant data were reviewed; none of eight with comparisons indicated that Alzheimer's disease-like neuropathology was more likely to be found in the brains of patients with schizophrenia than in the brains of comparison subjects. Suggestions that cerebral plaques and neurofibrillary tangles are more common in schizophrenia in association with neuroleptic treatment were not supported.

97 Ischemia with open blood-brain barrier and circulating human β-amyloid peptide trigger Alzheimer's disease-like neuropathology

97 Ischemia with open blood-brain barrier and circulating human β-amyloid peptide trigger Alzheimer's disease-like neuropathology

Increased messenger RNA expression of the 695 and 751 amino acid isoforms of the β-amyloid protein precursor in the thalamus of 17-year-old cynomolgus (Macaca fascicularis) monkeys

The levels of expression of messenger RNAs of the 695 and 751 amino acid isoforms of the beta-amyloid protein precursor in the brains of three-year-old and 17-year-old cynomolgus monkeys (Macaca fascicularis) were visualized and quantified by in situ hybridization histochemistry using 35S-labelled oligonucleotide probes. The analysis was carried out on coronal brain sections taken through the hippocampus and thalamus at the level of the geniculate nuclei. High densities of beta-amyloid protein precursor695 and beta-amyloid protein precursor751 messenger RNAs were found in the medial aspects of the mediodorsal, centromedian and parafascicular nuclei of the 17-year-old monkeys. The messenger RNA levels of the 695 and 751 isoforms were about two- and seven-fold, respectively, those found in the same nuclei of the three-year-old animals. The levels of these messenger RNA transcripts in the 17-year-old monkeys were not significantly different from those in the three-year-old animals in other brain areas e.g. the temporal cortex, entorhinal cortex and hippocampus. No Alzheimer's disease-like neuropathology in terms of diffuse or senile beta-amyloid plaques, dystrophic neurites or neurofibrillary tangles were detectable by specific innumohistochemical procedures in the above thalamic nuclei of the 17-year-old animals. In addition no reactive gliosis was seen in the thalamus of these monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)