Solvent effects on beta protein toxicity in vivo

Waite, Jerene J.; Cole, Greg M.; Frautschy, Sally A.; Connor, D.J.; Thal, Leon J.

doi:10.1016/0197-4580(92)90062-3

Cited by 83 publications

(57 citation statements)

References 11 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: 69%

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: 69%

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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“…A␤ has been reported to exert a variety of toxic effects on neurons both in vitro (7,8) and in vivo (9). However, it has been reported that mice overproducing A␤1-42 extracellularly showed no neuronal loss (10), thus suggesting that A␤ peptide seems not to be the only constituent in neurotoxicity associated to AD.…”

mentioning

confidence: 94%

Amyloid Precursor Protein Family-induced Neuronal Death Is Mediated by Impairment of the Neuroprotective Calcium/Calmodulin Protein Kinase IV-dependent Signaling Pathway

Mbebi¹,

Sée²,

Mercken³

et al. 2002

Journal of Biological Chemistry

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The aberrant metabolism of ␤-amyloid precursor protein (APP) and the progressive deposition of its derived fragment ␤-amyloid peptide are early and constant pathological hallmarks of Alzheimer's disease. Because APP is able to function as a cell surface receptor, we investigated here whether a disruption of the normal function of APP may contribute to the pathogenic mechanisms in Alzheimer's disease. To this aim, we generated a specific chicken polyclonal antibody directed against the extracellular domain of APP, which is common with the ␤-amyloid precursor-like protein type 2. Exposure of cultured cortical neurons to this antibody (APP-Ab) induced cell death preceded by neurite degeneration, oxidative stress, and nuclear condensation. Interestingly, caspase-3-like protease was not activated in this neurotoxic action suggesting a different mode of cell death than classical apoptosis. Further analysis of the molecular mechanisms revealed a calpain-and calcineurindependent proteolysis of the neuroprotective calcium/ calmodulin-dependent protein kinase IV and its nuclear target protein cAMP responsive element binding protein. These effects were abolished by the G protein inhibitor pertussis toxin, strongly suggesting that APP binding operates via a GTPase-dependent pathway to cause neuronal death. Alzheimer's disease (AD)1 is a devastating neurodegenerative disorder characterized by deposition of ␤-amyloid (A␤) plaques, accumulation of intracellular neurofibrillary tangles, and neuronal cell loss (1). A␤ peptide is generated by proteolysis of the amyloid precursor protein (APP), which is the product of a gene located on human chromosome 21 and on mouse chromosome 16. APP is expressed in most mammalian tissues (2, 3) and is present in at least 10 different spliced variants (4). In the brain, the major isoform generating A␤ is a peptide consisting of 695 residues that contains a single transmembrane domain (5). Although the physiological role of APP is still unclear, several studies have suggested that it is implicated in important physiological functions of neurons, such as neurite outgrowth, synaptogenesis, cell substrate adhesion and neuronal survival (for review see Ref. 6).Up to now, most of the research has been focused on the toxicity of A␤ peptide related to AD. A␤ has been reported to exert a variety of toxic effects on neurons both in vitro (7,8) and in vivo (9). However, it has been reported that mice overproducing A␤1-42 extracellularly showed no neuronal loss (10), thus suggesting that A␤ peptide seems not to be the only constituent in neurotoxicity associated to AD. Previous studies have demonstrated that overexpression of full-length APP induced degeneration of postmitotic neurons derived from embryonal carcinoma cells (11). Moreover, intracellular accumulation of wild-type APP in the rat hippocampus caused a specific type of neuronal degeneration in vivo in the absence of extracellular A␤ deposition (12), and viral vector-mediated overexpression of wild-type APP induced apoptosis-like death of neurons...

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“…Overproduction of Ah and its deposition into senile plaques are also frequently observed in sporadic AD cases (Ray et al, 1998;Saido, 1998). Moreover, Ah peptides exert neurotoxic effects in various systems (Loo et al, 1993;Mattson et al, 1993;Pike et al, 1995;Waite et al, 1992;Yankner et al, 1990). It is not entirely clear, however, how Ah contributes to the development of AD.…”

Section: Introductionmentioning

confidence: 99%