Intracerebral /sB-amyloid(25–35) produces tissue damage: Is it neurotoxic?

Rush, Douglas K.; Aschmies, Suzann; Merriman, Michael C.

doi:10.1016/0197-4580(92)90061-2

Cited by 72 publications

(31 citation statements)

References 12 publications

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“…Specifically, fibrils were generated consistently from A␤1-40 but not from A␤1-42. Although previous in vivo studies (Rush et al, 1992;Snow et al, 1994) reported the formation of amyloid fibrils in the rat brain after injections of A␤1-40, and other in vivo studies (Waite et al, 1992) of injections of A␤1-42 failed to produce amyloid fibrils, our study is novel because it directly assessed the differential amyloidogenic capabilities of these two important species of A␤ in vivo, and this has enabled us to reconcile a critical discrepancy in the literature on amyloidogenesis in the AD brain. Indeed, our data are consistent with studies showing that A␤C42 dominates in diffuse plaques with few amyloid fibrils (Yamaguchi et al, 1989;Davies and Mann, 1993;Iwatsubo et al, 1994Iwatsubo et al, , 1995, whereas A␤C40 is most prominent in cored plaques with abundant amyloid fibrils (Iwatsubo et al, 1994.…”

Section: Discussionmentioning

confidence: 74%

Amyloid β-Protein (Aβ) 1–40 But Not Aβ1–42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain

et al. 1997

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Two major C-terminal variants ending at Val40 and Ala42 constitute the majority of amyloid ␤-protein (A␤), which undergoes postsecretory aggregation and deposition in the Alzheimer disease (AD) brain. To probe the differential pathobiology of the two A␤ variants, we used an in vivo paradigm in which freshly solubilized A␤1-40 or A␤1-42 was injected into rat brains, followed by examination using Congo red birefringence, A␤ immunohistochemistry, and electron microscopy. In the rat brain, soluble A␤ 1-40 and A␤1-42 formed aggregates, and the A␤1-40 but not the A␤1-42 aggregates showed Congo red birefringence. Electron microscopy revealed that the A␤1-40 aggregates contained fibrillar structures similar to the amyloid fibrils of AD, whereas the A␤1-42 aggregates contained nonfibrillar amorphous material. Preincubation of A␤1-42 solution in vitro led to the formation of birefringent aggregates, and after injection of the preincubated A␤1-42, the aggregates remained birefringent in the rat brain. Thus, a factor or factors might exist in the rat brain that inhibit the fibrillar assembly of soluble A␤1-42. To analyze the postsecretory processing of A␤, we used the same in vivo paradigm and showed that A␤1-40 and A␤1-42 were processed at their N termini to yield variants starting at pyroglutamate, and at their C termini to yield variants ending at Val40 and at Val39. Thus the normal rat brain could produce enzymes that mediate the conversion of A␤ 1-40/1-42 into processed variants similar to those in AD. This experimental paradigm may facilitate efforts to elucidate mechanisms of A␤ deposition evolving into amyloid plaques in AD.

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Section: Discussionmentioning

confidence: 74%

Amyloid β-Protein (Aβ) 1–40 But Not Aβ1–42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain

et al. 1997

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“…In primary neuronal cultures, aggregates of A,8P induce dystrophic neurite morphology (9) and neuronal loss (10)(11)(12). Further, in vivo studies have shown that intracerebral injection of ,&amyloid plaque cores and A(8P aggregates induce neuronal degeneration in adult rats and aged primates (13)(14)(15)(16)(17). Although experimental studies confirm the predicted neurotoxicity of A,BP, the mechanism(s) and molecular events of ApP-induced neuronal cell death have not been identified.…”

mentioning

confidence: 94%

Apoptosis is induced by beta-amyloid in cultured central nervous system neurons.

Loo

Copani

Pike

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

974

566

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The molecular mechanism responsible for the neurodegeneration in Alzheimer disease is not known; however, accumulating evidence suggests that 3-amyloid peptide (A.8P) contributes to this degeneration. We now report that synthetic A3Ps trigger the degeneration of cultured neurons through activation of an apoptotic pathway. Neurons treated with AIIPs exhibit morphological and biochemical characteristics of apoptosis, including membrane blebbing, compaction of nuclear chromatin, and internucleosomal DNA fragmenta- This idea is consistent with the fact that cultured cells that express a familial AD-linked mutated form of A,8PP produce severalfold more APP than cells expressing the normal A,8PP

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“…Many lines of evidence indicate that A␤, a 39 -43 amino acid, the proteolytically derived fragment of APP, that is a principal constituent of senile plaques, may play an important role in the pathogenesis of AD (Selkoe, 1994). A␤ has been reported to be toxic to neurons in vitro (Yankner et al, 1990;Busciglio et al, 1992;Mattson et al, 1993;Pike et al, 1993;Behl et al, 1994;Iversen et al, 1995) and in vivo (Kowall et al, 1991;Frautschy et al, 1991;Rush et al, 1992;Waite et al, 1992). The toxicity of A␤ has been reported to be related with some intrinsic ion channel activity (Mattson et al, 1992), reactive oxygen species (Behl et al, 1994) and alteration of neurotransmitter receptor function (Yankner et al, 1990).…”

mentioning

confidence: 98%

APP carboxyl-terminal fragment without or with A? domain equally induces cytotoxicity in differentiated PC12 cells and cortical neurons

et al. 2000

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Mutations in the beta-amyloid precursor protein (APP) gene cause familial Alzheimer's disease (AD). Although amyloid beta peptide (Abeta) is the principal constituent of senile plaques in AD, other cleavage products of APP are also implicated in playing a role in the pathogenesis of AD. C-terminal fragments of APP (APP-CTs), that contain complete Abeta sequence, are found in neuritic plaques, neurofibrillary tangles and the cytosol of lymphoblastoid cells obtained from AD patients. Our previous report demonstrated that APP-CT105 causes death of differentiated PC12 cells and cultured rat cortical neurons (Kim and Suh [1996] J. Neurochem. 67:1172-1182) and induces strong inward currents in Xenopus oocyte (Fraser et al., [1996] J. Neurochem. 66:2034-2040). In the present study, to investigate which domain of APP-CT105 is responsible for the neurotoxicity, we have made deletion mutants of APP-CT105 without Abeta and transmembrane domain (TM) or without NPTY domain, a putative endocytosis signaling sequence, using the PCR-amplified strategy and the recombinant GST-fusion protein strategy. The effect on cell survival of the deletion mutants of APP-CT105 (8 microM) was then determined by the LDH and MTT assay. We found that C-terminal fragment without NPTY significantly causes cell death in NGF-differentiated PC12 cells and cultured rat cortical neurons. This finding suggests that NPTY may not play an important role in APP-CT105 mediated neurotoxicity. We found, however, that C-terminal fragment without Abeta and TM significantly induces neuronal cell death. Our results suggest that in addition to Abeta, C-terminal fragment of APP without Abeta and TM domain itself may also participate in the neuronal degeneration in AD.

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Intracerebral /sB-amyloid(25–35) produces tissue damage: Is it neurotoxic?

Cited by 72 publications

References 12 publications

Amyloid β-Protein (Aβ) 1–40 But Not Aβ1–42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain

Amyloid β-Protein (Aβ) 1–40 But Not Aβ1–42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain

Apoptosis is induced by beta-amyloid in cultured central nervous system neurons.

APP carboxyl-terminal fragment without or with A? domain equally induces cytotoxicity in differentiated PC12 cells and cortical neurons

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