Much evidence indicates that abnormal processing and extracellular deposition of amyloid-beta peptide (A beta), a proteolytic derivative of the beta-amyloid precursor protein (betaAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with A beta causes a marked reduction in burden of the brain amyloid. Evidence that A beta immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal A beta processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the 'amyloid cascade'. Here we show that A beta immunization reduces both deposition of cerebral fibrillar A beta and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of A beta in the brain. This implies that either a approximately 50% reduction in dense-cored A beta plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic A beta species.

We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid ␤-peptide (A␤) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL؉V717F) under the control of the PrP gene promoter. Thioflavine S-positive A␤ amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200 -4,600 pmol of A␤42 per g brain at age 6 months, with an excess of A␤42 over A␤40. High level production of the pathogenic A␤42 form of A␤ peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against A␤42

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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.

Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-␤ (A␤) peptide. To explore this relationship in vivo, toxic-milk (tx J ) mice with a mutant ATPase7b transporter favoring elevated Cu levels were analyzed in combination with the transgenic (Tg) CRND8 amyloid precursor protein mice exhibiting robust A␤ deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive tx J mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma A␤ levels. In addition, homozygosity for tx J increased survival of young TgCRND8 mice and lowered endogenous CNS A␤ at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the tx J mutation on CNS A␤ burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of A␤ peptide. A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by extracellular deposition of amyloid-␤ (A␤) as senile plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles (1). A␤ is generated by secretase-mediated endoproteolysis of the amyloid precursor protein (APP), and familial AD mutations skew APP processing to favor production of pro-amyloidogenic forms of the peptide or net A␤ production and thus drive disease pathogenesis. Although there is growing interest in defining pathogenic subvarieties of A␤ [e.g., secreted oligomeric assemblies such as A␤-derived diffusible ligands (2) and intracellular forms (3)], modulators of APP and A␤ biology in sporadic disease have remained more elusive. One area of particular interest concerns the role of transition metals.Cu and Zn ions are abundant in the normal brain (4-6), and direct measurements of metal levels have indicated altered homeostasis in AD (7-10). Interestingly, APP has a selective, high-affinity Cu-binding site in the extracellular (ecto-) domain that is capable of reducing Cu(II) to Cu(I) (11), and a recent structural analysis of this domain has revealed some similarity to previously identified Cu chaperone proteins (12). In addition to the ectodomain Cu-binding site of APP, A␤ peptide also contains binding sites for . A␤-metal interaction may drive both fibril formation and free radical production (13,(16)(17)(18), findings potentially relevant to AD pathogenesis in vivo, given that metal chelators can resolubilize A␤ aggregates from postmortem AD brain (19). On the other hand, studies of APP processing in cultured cells have revealed stimulation of the ␣-secretase pathway for APP processing by extracellular Cu ions (20). As this pathway cleaves the A␤ domain of APP into two fragments, it has a potential to be anti-amyloidogenic. Prompted by these divergent observations, we devised a genetic experiment to investigate how Cu might modulate A␤-dependent pathologies in vivo by using the transgenic (Tg) CRND8 line of TgAPP mice (21,22) in conjunction with a mutant allele of the CuATPase7b c...

While PrPC rearranges in the area of codons 104 -113 to form PrP Sc during prion infections, the events that initiate sporadic Creutzfeldt-Jakob disease are undefined. As Cu(II) is a putative ligand for PrP C and has been implicated in the pathogenesis of Creutzfeldt-Jakob disease and other neurodegenerative diseases, we investigated the structural effects of binding. Incubation of brain microsomes with Cu(II) generated ϳ30-kDa proteinase K-resistant PrP. Cu(II) had little effect on fresh recombinant PrP23-231, but aged protein characterized by conversion of Asn-107 to Asp decreased ␣-helical content by ϳ30%, increased ␤-sheet content 100%, formed aggregates, and acquired proteinase K resistance in the presence of Cu(II). These transitions took place without need for acid pH, organic solvents, denaturants, or reducing agents. Since conversion of Asn to Asp proceeds by a spontaneous pathway involving deamidation, our data suggest that covalent variants of PrP C arising in this manner may, in concert with Cu(II), generate PrP Sc -like species capable of initiating sporadic prion disease.

Objective— Severe heatstroke is a leading cause of morbidity and mortality during heat waves. The pathogenesis of tissue injury, organ failure, and death in heatstroke is not well understood. Methods and Result— We investigated the pathways of heatstroke-induced tissue injury and cell death in anesthetized baboons ( Papio hamadyras ) subjected to environmental heat stress until core temperature attained 42.5°C (moderate heatstroke; n=3) or onset of severe heatstroke (n=4) signaled by a fall in systolic blood pressure to <90 mm Hg and rise in core temperature to 43.1±0.1°C. Three sham-heated animals served as controls. Light and electron microscopy revealed widespread hemorrhage and thrombosis, transmural migration of leukocytes, and microvascular endothelium injury in severe heatstroke. Immunohistology and ultrastructural analysis demonstrated increased staining of endothelial von Willebrand factor (vWF), tissue factor (TF), and endothelial leukocyte-platelet interaction. Extensive apoptosis was noted in spleen, gut, and lung, and in hematopoeitic cells populating these organs. Double-labeling studies colocalized active caspase-3 and TF with apoptotic cells. Findings in sham-heated animals were unremarkable. Conclusion— These data suggested that microvascular injury, thrombosis, inflammation, and apoptosis may play an important role in the pathogenesis of heatstroke injury.

Missense mutations of the tau gene cause autosomal dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory loss between 10 to 12 months of age. These findings suggested that TgTauR406W mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimer's disease (AD).