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Background: Microglial activation has been proposed to facilitate clearance of amyloid β protein (Aβ) from the brain following Aβ immunotherapy in amyloid precursor protein (APP) transgenic mice. Interleukin-1 receptor 1 knockout (IL-1 R1-/-) mice are reported to exhibit blunted inflammatory responses to injury. To further define the role of IL-1-mediated inflammatory responses and microglial activation in this paradigm, we examined the efficacy of passive Aβ immunotherapy in Tg2576 mice crossed into the IL-1 R1-/- background. In addition, we examined if loss of IL-1 R1-/- modifies Aβ deposition in the absence of additional manipulations. Methods: We passively immunized Tg2576 mice crossed into the IL-1 R1-/- background (APP/IL-1 R1-/- mice) with an anti-Aβ1-16 mAb (mAb9, IgG2a) that we previously showed could attenuate Aβ deposition in Tg2576 mice. We also examined whether the IL-1 R1 knockout background modifies Aβ deposition in untreated mice. Biochemical and immunohistochemical Aβ loads and microglial activation was assessed. Results: Passive immunization with anti-Aβ mAb was effective in reducing plaque load in APP/IL-1 R1-/- mice when the immunization was started prior to significant plaque deposition. Similar to previous studies, immunization was not effective in older APP/IL-1 R1-/- mice or IL-1 R1 sufficient wild type Tg2576 mice. Our analysis of Aβ deposition in the untreated APP/IL-1 R1-/- mice did not show differences on biochemical Aβ loads during normal aging of these mice compared to IL-1 R1 sufficient wild type Tg2576 mice. Conclusion: We find no evidence that the lack of the IL-1 R1 receptor influences either Aβ deposition or the efficacy of passive immunotherapy. Such results are consistent with other studies in Tg2576 mice that suggest microglial activation may not be required for efficacy in passive immunization approaches. [ABSTRACT FROM AUTHOR]

Accumulation and aggregation of amyloid beta peptide 1-42 (Abeta42) in the brain has been hypothesized as triggering a pathological cascade that causes Alzheimer disease (AD). To determine whether selective targeting of Abeta42 versus Abeta40 or total Abeta is an effective way to prevent or treat AD, we compared the effects of passive immunization with an anti-Abeta42 mAb, an anti-Abeta40 mAb, and multiple Abeta(1-16) mAbs. We established in vivo binding selectivity of the anti-Abeta42 and anti-Abeta40 mAbs using novel TgBRI-Abeta mice. We then conducted a prevention study in which the anti-Abeta mAbs were administered to young Tg2576 mice, which have no significant Abeta deposition, and therapeutic studies in which mAbs were administered to Tg2576 or CRND8 mice with modest levels of preexisting Abeta deposits. Anti-Abeta42, anti-Abeta40, and anti-Abeta(1-16) mAbs attenuated plaque deposition in the prevention study. In contrast, anti-Abeta42 and anti-Abeta40 mAbs were less effective in attenuating Abeta deposition in the therapeutic studies and were not effective in clearing diffuse plaques following direct injection into the cortex. These data suggest that selective targeting of Abeta42 or Abeta40 may be an effective strategy to prevent amyloid deposition, but may have limited benefit in a therapeutic setting. [ABSTRACT FROM AUTHOR]

The article provides information on the findings of a study on the mechanisms of action of anti-Aβ antibodies in Alzheimer's disease mouse model. A stable monoclonal antibodies (mAbs):Aβ complex is created by peripheral administration of anti-mAb in the plasma. The half-life of plasma Aβ is prolonged from minutes to days by binding mAbs to Aβ.

Selective lowering of Aβ42 levels (the 42-residue isoform of the amyloid-β peptide) with small-molecule γ-secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer’s disease. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the γ-secretase complex, but instead labelled the β-amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid-β peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP γ-secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28–36 of amyloid-β, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid-β act as GSMs, and some GSMs alter the production of cell-derived amyloid-β oligomers. Furthermore, mutation of the GSM binding site in the APP alters the sensitivity of the substrate to GSMs. These findings indicate that substrate targeting by GSMs mechanistically links two therapeutic actions: alteration in Aβ42 production and inhibition of amyloid-β aggregation, which may synergistically reduce amyloid-β deposition in Alzheimer’s disease. These data also demonstrate the existence and feasibility of ‘substrate targeting’ by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of ‘druggable’ targets. [ABSTRACT FROM AUTHOR]

Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid β precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer's disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-Aβ1- 40 transgenes in APP mouse models. Expression of BRI2-Aβ1- 40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild-type human BRI2 reduces cerebral Aβ deposition in an AD mouse model. Additional data indicate that the 23 aa peptide, Bri23, released from BRI2 by normal processing, is present in human CSF, inhibits Aβ aggregation in vitro and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of Aβ deposition in vivo. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized by a decline in cognitive function and accumulation of amyloid-β peptide (Aβ) in extracellular plaques. Mutations in amyloid precursor protein (APP) and presenilins alter APP metabolism resulting in accumulation of Aβ42, a peptide eβential for the formation of amyloid deposits and proposed to initiate the cascade leading to AD. However, the role of Aβ40, the more prevalent Aβ peptide secreted by cells and a major component of cerebral Aβ deposits, is leβ clear. In this study, virally-mediated gene transfer was used to selectively increase hippocampal levels of human Aβ42 and Aβ40 in adult Wistar rats, allowing examination of the contribution of each to the cognitive deficits and pathology seen in AD. Results: Adeno-aβociated viral (AAV) vectors encoding BRI-Aβ cDNAs were generated resulting in high-level hippocampal expreβion and secretion of the specific encoded Aβ peptide. As a comparison the effect of AAV-mediated overexpreβion of APPsw was also examined. Animals were tested for development of learning and memory deficits (open field, Morris water maze, paβive avoidance, novel object recognition) three months after infusion of AAV. A range of impairments was found, with the most pronounced deficits observed in animals co-injected with both AAV-BRI-Aβ40 and AAV-BRI-Aβ42. Brain tiβue was analyzed by ELISA and immunohistochemistry to quantify levels of detergent soluble and insoluble Aβ peptides. BRI-Aβ42 and the combination of BRI-Aβ40+42 overexpreβion resulted in elevated levels of detergentinsoluble Aβ. No significant increase in detergent-insoluble Aβ was seen in the rats expreβing APPsw or BRI-Aβ40. No pathological features were noted in any rats, except the AAV-BRI-Aβ42 rats which showed focal, amorphous, Thioflavin-negative Aβ42 deposits. Conclusion: The results show that AAV-mediated gene transfer is a valuable tool to model aspects of AD pathology in vivo, and demonstrate that whilst expreβion of Aβ42 alone is sufficient to initiate Aβ deposition, both Aβ40 and Aβ42 may contribute to cognitive deficits. [ABSTRACT FROM AUTHOR]