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.

One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with human amyloid beta-peptide reduces plaque burden and its associated pathologies. Several hypotheses have been proposed regarding the mechanism of this response. Here we report that peripheral administration of antibodies against amyloid beta-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid beta-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.

The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A beta 42 peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid beta-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels, alpha- and beta-secretase activity and A beta production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in A beta 42 secretion in all mutant clones. Likewise, mutant but not wildtype PS1 transgenic mice showed significant overproduction of A beta 42 in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on A beta generation. The extent of A beta 42 increase did not correlate with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing A beta 42 production, thus promoting cerebral beta-amyloidosis.

The PDAPP transgenic mouse, which overexpresses human amyloid precursor protein (APP717V3F), has been shown to develop much of the pathology associated with Alzheimer disease. In this report, levels of APP and its amyloidogenic metabolites were measured in brain regions of transgenic mice between 4 and 18 months of age. While absolute levels of APP expression likely contribute to the rate of amyloid ␤-peptide (A␤) deposition, regionally specific factors also seem important, as homozygotic mice express APP levels in pathologically unaffected regions in excess of that measured in certain amyloid plaque-prone regions of heterozygotic mice. Regional levels of APP and APP-␤ were nearly constant at all ages, while A␤ levels dramatically and predictably increased in brain regions undergoing histochemically confirmed amyloidosis, most notably in the cortex and hippocampus. In hippocampus, A␤ concentrations increase 17-fold between the ages of 4 and 8 months, and by 18 months of age are over 500-fold that at 4 months, reaching an average level in excess of 20 nmol of A␤ per g of tissue. A␤ 1-42 constitutes the vast majority of the depositing A␤ species. The similarities observed between the PDAPP mouse and human Alzheimer disease with regard to A␤ 42 deposition occurring in a temporally and regionally specific fashion further validate the use of the model in understanding processes related to the disease.In the Alzheimer disease (AD) brain, region-specific amyloid ␤-peptide (A␤) amyloidosis is a key pathological feature and is accompanied by astrogliosis, microgliosis, cytoskeletal changes, and synaptic loss. These pathological alterations are thought to be linked to the cognitive decline that clinically defines the disease (1). AD primarily afflicts the elderly, although genetic mutations in the amyloid precursor protein (APP) gene have been described that accelerate the disease process and lower the average age of onset by decades, further supporting a fundamental role for this protein in the disease (2-5). Many questions remain about the spatial-temporal sequence of neuropathological events, particularly what factors are responsible for the selective vulnerability of certain brain regions to amyloidosis. Candidate mechanisms include constitutive increased production of A␤ in vulnerable areas, age-related changes in expression of APP and production of A␤, and inherent differences in the ability of different brain regions to clear or catabolize A␤. These fundamental issues are not easily addressed in human subjects.Similar neuropathology to that seen in human AD brain has been demonstrated in a transgenic mouse generated using a platelet-derived growth factor ␤ promoter driving a human APP minigene (6) and possessing the familial AD mutation V3F at APP position 717 (4) (PDAPP). These animals express high levels of APP and A␤, but more importantly they exhibit profuse A␤ amyloidosis, which, in an age-and brain region-specific manner, morphologically resembles that seen in AD. In addition, these mice develop marke...

In this clinical study the cerebrospinal fluid (CSF) level of a novel form of the beta-amyloid peptide (A beta) extending to position 42 (A beta 42) was determined in patients with Alzheimer's disease (AD) as well as controls. In addition to measurement of CSF A beta 42 levels, total A beta peptides, microtubule-associated protein tau, and apolipoprotein E (ApoE) genotype were also assessed. It is interesting that CSF A beta 42 levels were found to be significantly lower in AD patients relative to controls, whereas total A beta levels were not. A beta 42 has recently been shown to preferentially deposit in the brain tissue of patients with AD, suggesting that diminished clearance may account for its reduction in CSF. As previously reported, tau levels were increased in AD patients; however, neither A beta 42 nor tau levels were apparently influenced by the ApoE genotype.