Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.

Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present study, transgenic animals were immunized with Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease.

Aggregated amyloid-beta protein induces cortical neuronal apoptosis and concomitant "apoptotic" pattern of gene induction.

To gain a molecular understanding of neuronal responses to amyloid-beta peptide (Abeta), we have analyzed the effects of Abeta treatment on neuronal gene expression in vitro by quantitative reverse transcription-PCR and in situ hybridization. Treatment of cultured rat cortical neurons with Abeta1-40 results in a widespread apoptotic neuronal death. Associated with death is an induction of several members of the immediate early gene family. Specifically, we (1) report the time-dependent and robust induction of c-jun, junB, c-fos, and fosB, as well as transin, which is induced by c-Jun/c-Fos heterodimers and encodes an extracellular matrix protease; these gene inductions appear to be selective because other Jun and Fos family members, i.e., junD and fra-1, are induced only marginally; (2) show that the c-jun induction is widespread, whereas c-fos expression is restricted to a subset of neurons, typically those with condensed chromatin, which is a hallmark of apoptosis; (3) correlate gene induction and neuronal death by showing that each has a similar dose-response to Abeta; and (4) demonstrate that both cell death and immediate early gene induction are dependent on Abeta aggregation state. This overall gene expression pattern during this "physiologically inappropriate" apoptotic stimulus is markedly similar to the pattern we previously identified after a "physiologically appropriate" stimulus, i.e., the NGF deprivation-induced death of sympathetic neurons. Hence, the parallels identified here further our understanding of the genetic alterations that may lead neurons to apoptosis in response to markedly different insults.

Amyloid beta-mediated oxidative and metabolic stress in rat cortical neurons: no direct evidence for a role for H2O2 generation.

H2O2 and free radical-mediated oxidative stresses have been implicated in mediating amyloid beta (1-40) [A beta (1-40)] neurotoxicity to cultured neurons. In this study, we confirm that addition of the H2O2-scavenging enzyme catalase protects neurons in culture against A beta-mediated toxicity; however, it does so by a mechanism that does not involve its ability to scavenge H2O2. A beta-mediated elevation in intracellular H2O2 production is suppressed by addition of a potent H2O2 scavenger without any significant neuroprotection. Three intracellular biochemical markers of H2O2-mediated oxidative stress were unchanged by A beta treatment: (a) glyceraldehyde-3-phosphate dehydrogenase activity, (b) hexose monophosphate shunt activity, and (c) glucose oxidation via the tricarboxylic acid cycle. lonspray mass spectra of A beta in the incubation medium indicated that A beta itself is an unlikely source of reactive oxygen species. In this study we demonstrate that intracellular ATP concentration is compromised during the first 24-h exposure of neurons to A beta. Our results challenge a pivotal role for H2O2 generation in mediating A beta toxicity, and we suggest that impairment of energy homeostasis may be a more significant early factor in the neurodegenerative process.