Expression of a carboxy-terminal region of the β-amyloid precursor protein in a heterogeneous culture of neuroblastoma cells: evidence for altered processing and selective neurotoxicity

Fukuchi, Ken Ichiro; Kamino, Kouzin; Deeb, Samir S.; Furlong, Clement E.; Sundstrom, Joseph A.; Smith, Anthony; Martin, George M.

doi:10.1016/0169-328x(92)90191-d

Cited by 45 publications

(30 citation statements)

References 21 publications

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“…It has been reported that amyloidogenic CT fragments of /IAPP appear to be toxic to neurons in culture (Yankner et al, 1989;Fukuchi et al, 1992aFukuchi et al, , 1993aHayashi et al, 1992;Yoshikawa et al, 1992;Sopher et al, 1994), in transgenic mice Arters et al, 1995;Oster-Granite et al, 1996), and in the brains of mice transplanted with CTtransfcctcd cells (Table 3).…”

Section: Channel (Pore)-forming Activities and Neurotoxicity Of Ct Frmentioning

confidence: 99%

“…PC12 cells stably transfected with CT 100 gradually degenerated only when induced to differentiate into neuronal cells by nerve growth factor (NGF) (Yankner et al, 1989). Neurons but not nonneuronal cells derived from a multipotent embryonic carcinoma cell line (P19 cells) and a morphologically heterogeneous neuroblastoma cell line (SK-N-SH) were vulnerable to overexpression of CT 99 (Fukuchi et al, 1992a(Fukuchi et al, , 1993a. have recently found that amyloidogenic CT 105 directly damaged the cortical neurons and PC12 cells but did not affect the viability of U 251 cells originating from human glioblastoma, suggesting a neuroselective toxic effect of CT 105.…”

Section: Neuronal Specificity Of Ct Fragment Toxicitymentioning

confidence: 99%

“…heterogeneous neuroblastoma cell line (SK-N-SH) were vulnerable to overexpression of CT 99 (Fukuchi et al, 1992a(Fukuchi et al, , 1993a. have recently found that amyloidogenic CT 105 directly damaged the cortical neurons and PC12 cells but did not affect the viability of U 251 cells originating from human glioblastoma, suggesting a neuroselective toxic effect of CT 105.…”

Section: Ct Fragments Of /Iapp In Ad 1785mentioning

confidence: 99%

“…CT fragments with molecular masses of 12-16 kDa have also been found in media and cytosol of lymphoblastoid cells obtained from patients with earlyor late-onset FAD (Matsumoto, 1994) and Down's syndrome (Kametani et al, 1994). Finally, several transfection studies have correlated production of the A/I-bearing CT fragment with neurotoxicity (Yankner et al, 1989;Fukuchi et al, 1992a Fukuchi et al, ,b, 1993Neve et al, 1992;Yoshikawa et al, 1992); whereas recent transgenic animal experiments using CT 100 peptide have linked CT fragment production with neurodegeneration Arters et al, 1995;Howland et al, 1995;Oster-Granite et al, 1996).In addition, this amyloidogenic CT peptide is expressed not only in the extracellular fluid of some FAD and Down' s syndrome cells but is also secreted in the media of PCI2 cells transfected with CT 104 and human mixed-brain cell cultures (Yankner et al, 1989;Seubert et al, 1993;Matsumoto, 1994;.It has been recently demonstrated that either extracellular or intracellular application of CT 105 elicited strong nonselective inward currents and toxic effects in Xenopus oocytes (Fraser et al, 1996), in rat Purkinje neurons (Hartell and Suh, 1996), and in PC 12 and cultured rat cortical cells . The channel-inducing and toxic activity of CT 105 was much more potent than that of any A/I fragments.…”

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An Etiological Role of Amyloidogenic Carboxyl‐Terminal Fragments of the β‐Amyloid Precursor Protein in Alzheimer's Disease

Suh

1997

Journal of Neurochemistry

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Amyloid~3protein (A/3), 39-43 amino acids long, is the principal constituent of the extracellular amybid deposits in brain that are characteristic of Alzheimer's disease (AD). Several lines of evidence indicate that A~3 may play an important role in the pathogenesis of AD. However, there are several discrepancies between the production of A/3 and the development of the disease. Thus, A/may not be the sole active fragment of~3-amybid precursor protein (~3APP) in the neurotoxicity associated with AD. Consequently, the possible effects of other cleaved products of /3APP need to be explored. The recent concentration on other potentially amyloidogenic products of /IAPP has produced interesting candidates, the most promising of which are the amyloidogenic carboxyl-terminal (CT) fragments of~3APP. This review discusses a possible etiological role of CT fragments of /3APP in AD. Key Words: Amyloid precursor proteinCarboxyl-terminal peptide-Amyloid /3 protein -Etiological role-Alzheimer's disease. J. Neurochem. 68, 1781Neurochem. 68, -1791Neurochem. 68, (1997.Alzheimer' s disease (AD) is characterized by amybid deposits in senile plaques, in neurofibrillary tangles, and on the walls of cerebral blood vessels and dystrophic neurites, gliosis, and loss of neuronal synapses. various evidence indicates that amyloid~3pro-tein (A/3), which is a principal constituent of senile plaques (Glenner and Wong, 1984), may play an important role in the pathogenesis of AD (for review, see Selkoe, 1994;Checler, 1995). The A/I is composed of 39-43 amino acids and proteolytically derived from larger /3-amyloid precursor protein (/3APP) isoforms of 695, 714, 751, and 770 amino acids (Kang et al., 1987). Several mutations of /IAPP around the A/I domain have been discovered in certain types of earlyonset familial AD (FAD) (for review, see Tanzi et al., 1993), supporting its causal role in the pathogenesis of AD.To date, at least three processing pathways have been described: the nonamyloidogenic secretory pathway (a-secretase), which releases soluble ectodomain and prevents A/I formation (Esch et al., 1990); the endosomal-lysosomal pathway, in which some cell surface /IAPPs are reinternalized (Haass et al., 1 992a,b) and cleaved around at the N-terminus of the A/I sequence by /3-secretase to produce A/3-bearing amyloidogenic breakdown products of various sizes (14-22 kDa) Golde et al., 1992; Haass et al., 1992a,b;Shoji et al., 1992;Tamaoka et al., 1992) and subsequently possibly cleaved by 'ysecretase to release soluble 4-kDa A/I (Koo and Squazzo, 1994); and the 4-kDa A/I-producing pathway (/3-and y-secretases), involving coated pit-mediated endocytosis, which may be independent of the constitutive secretory pathway (Koo and Squazzo, 1994).Classically, A/I is the marker for AD, and it has been linked to the accompanying neurodegeneration (see, e.g., Sisodia et al., 1990). Several lines of evidence suggest that the overexpression of /3APP and the subsequent production of A/I could be linked to the genesis of AD (for review, see ...

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Section: Channel (Pore)-forming Activities and Neurotoxicity Of Ct Frmentioning

confidence: 99%

Section: Neuronal Specificity Of Ct Fragment Toxicitymentioning

confidence: 99%

Section: Ct Fragments Of /Iapp In Ad 1785mentioning

confidence: 99%

mentioning

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An Etiological Role of Amyloidogenic Carboxyl‐Terminal Fragments of the β‐Amyloid Precursor Protein in Alzheimer's Disease

Suh

1997

Journal of Neurochemistry

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Induction of connexin43 and gap junctional communication in PC12 cells overexpressing the carboxy terminal region of amyloid precursor protein

et al. 1996

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Human IMR‐32 neuroblastoma cells as a model cell line in Alzheimer's disease research

Neill

Hughes

Edwardson

et al. 1994

J of Neuroscience Research

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The present study investigated expression and processing of amyloid precursor protein by neuronally differentiated IMR-32 neuroblastoma cells. APP mRNA in these cells was found to consist of approximately 58% APP695, 38% APP751, and < 4% APP770. APP-immunoreactive bands detected in western blots of cellular protein extracts were only detected by anti-APP antibodies to peptides with strong homology to APLP2, suggesting that these bands represent APP-like proteins and not APP itself. This result suggests that previous studies claiming immunodetection of cellular forms of APP may have to be re-evaluated. Four main species of C-terminal truncated, secreted APP were detected in blots of protein extracts from medium conditioned by these cells. The immunoreactive profile of these bands suggested a cleavage site N-terminal to the Lys16-Leu17 bond of alpha-secretase. This, together with differences in number and molecular mass of APP-immunoreactive bands between secreted APP from IMR-32 cells and that from the commonly used PC-12 cells, suggests differences in APP processing between these two neuronally differentiated cell lines. In theory, IMR-32 cells being of human neuronal origin may be a more appropriate cell line to study APP-processing in relation to Alzheimer's disease than the rat phaeochromocytoma PC-12 cell line. Therefore, these detected differences warrant further investigation. Additionally IMR-32 cells under certain tissue culture conditions can form intracellular fibrillary material that reacts with anti-PHF specific antibodies. Neuronally differentiated IMR-32 cells could therefore be used as a model system to investigate possible interactions between APP-processing and PHF formation.

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Expression of a carboxy-terminal region of the β-amyloid precursor protein in a heterogeneous culture of neuroblastoma cells: evidence for altered processing and selective neurotoxicity

Cited by 45 publications

References 21 publications

An Etiological Role of Amyloidogenic Carboxyl‐Terminal Fragments of the β‐Amyloid Precursor Protein in Alzheimer's Disease

An Etiological Role of Amyloidogenic Carboxyl‐Terminal Fragments of the β‐Amyloid Precursor Protein in Alzheimer's Disease

Induction of connexin43 and gap junctional communication in PC12 cells overexpressing the carboxy terminal region of amyloid precursor protein

Human IMR‐32 neuroblastoma cells as a model cell line in Alzheimer's disease research

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