Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer's disease.

Dyrks, Thomas; Weidemann, Andreas; Multhaup, Gerd; Salbaum, J. Michael; Lemaire, H. G.; Kang, Jie; Müller‐Hill, Benno; Masters, Colin L.; Beyreuther, Konrad

doi:10.1002/j.1460-2075.1988.tb02900.x

Cited by 368 publications

(170 citation statements)

References 34 publications

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“…In an aqueous environment above the critical micelle concentration, the OcGlc molecules form micelles with a polar surface made up from glucose head groups, which can mimic the glycoproteinor glycolipid-covered regions of the membrane surface. It was suggested that the primary event of amyloidogenesis in vivo is membrane damage (Dyrks et al, 1988). The presence of residual membrane particles nearby may help the stabilization of /?-pleated sheets, leading to a self-aggregation of human A4.…”

Section: Discussionmentioning

confidence: 99%

Human and rodent Alzheimer β‐amyloid peptides acquire distinct conformations in membrane‐mimicking solvents

Ötvös

Szendrei

Lee

et al. 1993

European Journal of Biochemistry

119

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The major constituent of senile plaques (one of the hallmark lesions of Alzheimer's disease) is a 42(43)-amino-acid polypeptide, termed the A4 or /3-amyloid peptide. The B-amyloid peptide or A4 is derived from one or more larger P-amyloid precursor proteins. The precursor protein from whence the A4 peptide is derived is highly conserved throughout evolution, and humans, monkeys, dogs, and bears develop brain deposits of A4 peptide in amyloid fibrils. However, similar accumulations of A4 amyloid are negligible in the brains of rats and mice for reasons that remain unexplored. Notably, the A4 sequence of rodents, deduced from the cDNA clones, differs only in three amino acids from the A4 isolated from the brain of humans. Hence, these differences could account for the inability of rodents to develop Alzheimer-like A4 amyloid plaques. To test this hypothesis directly, using physical and chemical model systems, we synthesized, purified, and characterized A4 peptides corresponding to the human and rodent sequences. Circular dichroic and Fourier-transform infrared spectroscopy were used with various membrane-mimicking solvents, different peptide concentrations, and variable pH to identify those environmental conditions that promoted B-pleated sheet formation of the human versus rodent A4. At an intermediate alkaline pH (< lo), the rodent peptide has more P-pleated sheet structure than the human sequence. The /I-pleated sheets for both peptides could be eliminated at very high pH ( 2 12). The amount of the p-structure increasedin an octyl glucoside solution, compared to that found in SDS, as well as in several of the other solutions tested here. This suggests that particles originated from prior membrane damage may play a role in the stabilization of /3-pleated sheets with subsequent formation of amyloid deposits. Finally, we found that higher P-pleated sheet content was observed for the rodent sequences in acetonitrile/water mixtures. In contrast, more P-

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Section: Discussionmentioning

confidence: 99%

Human and rodent Alzheimer β‐amyloid peptides acquire distinct conformations in membrane‐mimicking solvents

Ötvös

Szendrei

Lee

et al. 1993

European Journal of Biochemistry

119

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“…N-glycosylated and unglycosylated, forms of APP 695 (lane 2) and APP +1 (lane 3). APP 695 can be both N-and O-linked glycosylated (Dyrks et al 1988;Weidemann et al 1989;Oltersdorf et al 1990), whereas APP +1 , which lacks the sites for N-linked glycosylation is suggested to be O-glycosylated (Hersberger et al 2001). To exclude any cell type specific effects, transfection experiments were repeated on human neuronal cell-lines, i.e.…”

Section: Subcellular Localisation Of App +1 and App 695mentioning

confidence: 99%

Frame‐shifted amyloid precursor protein found in Alzheimer's disease and Down's syndrome increases levels of secreted amyloid β40

Dijk

Fischer

Sluijs

et al. 2004

Journal of Neurochemistry

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Frame-shifted amyloid precursor protein (APP +1 ), which has a truncated out-of-frame C-terminus, accumulates in the neuropathological hallmarks of patients with Alzheimer's disease pathology. To study a possible involvement of APP +1 in the pathogenesis of Alzheimer's disease, we expressed APP 695 and APP +1 in the HEK293 cell-line and studied whether the processing of APP 695 was affected. APP +1 is a secretory protein, but high expression of APP 695 and APP +1 results in the formation of intracellular aggregate-like structures containing both proteins and Fe65, an adaptor protein that interacts with APP 695 . APP +1 is shown to interact with APP 695 , suggesting that these structures consist of functional protein complexes. Such an interaction can also be anticipated in post-mortem brains of young Down's syndrome patients without any sign of neuropathology. Here we observed APP +1 immunoreactivity in beaded fibres. Additional support for functional consequences on the processing of APP 695 comes from a 1.4-fold increase in levels of secreted amyloid b 40 in cells co-expressing APP 695 and APP +1 , although APP +1 itself does not contain the amyloid b sequence. Taken together, these data show that co-expression of APP 695 and APP +1 affects the processing of APP 695 in a pro-amyloidogenic way and this could gradually contribute to Alzheimer's disease pathology, as has been implicated in Down's syndrome patients. Keywords: Alzheimer's disease, amyloid b, amyloid precursor protein, Down's syndrome, Fe65, protein interactions.

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“…A CT fragment of /IAPP that spans the A/I and cytoplasmic domains has a tendency to self-aggregate (Dyrks et al, 1988). Several sodium dodecyl sulfateresistant bands that were immunoreactive for CT antibody were observed on solubilization of the CT 105 peptide, indicating that this peptide has a strong tendency to self-aggregate .…”

Section: Amyloidogenicity Of Ct Fragmentsmentioning

confidence: 99%

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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Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer's disease.

Cited by 368 publications

References 34 publications

Human and rodent Alzheimer β‐amyloid peptides acquire distinct conformations in membrane‐mimicking solvents

Human and rodent Alzheimer β‐amyloid peptides acquire distinct conformations in membrane‐mimicking solvents

Frame‐shifted amyloid precursor protein found in Alzheimer's disease and Down's syndrome increases levels of secreted amyloid β40

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

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