Expression patterns of β‐amyloid precursor protein (β‐APP) in neural and nonneural human tissues from alzheimer's disease and control subjects

Arai, Hiroyuki; Lee, Virginia M.‐Y.; Messinger, Meridith L.; Greenberg, Barry D.; Lowery, David E.; Trojanowski, John Q.

doi:10.1002/ana.410300509

Cited by 151 publications

(87 citation statements)

References 31 publications

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“…Taken together, these results suggest that the Appa-RFP and Aplp2-RFP fusion proteins are not expressed in vascular cells, but instead are expressed in neurons, ganglia, and cells of the pronephros and are secreted. These results are consistent with studies of human β-APP that detected the presence of the proteins in neural tissues and only a few nonneural tissues, namely the pituitary and adrenal glands and cardiac muscle (Arai et al, 1991). The expression patterns in zebrafish indicate that following production in the neurons, the secreted Appa-RFP and Aplp2-RFP fusion proteins become enriched at the venous vessels in the embryo after 28 hpf.…”

Section: Secreted Appa-and Aplp2-rfp Fusion Proteins Accumulate At Thsupporting

confidence: 89%

“…It is also intriguing that patients with AD display reduced levels of the sAPPα cleavage peptide (Lannfelt et al, 1995), raising the possibility that the sAPPα could contribute to the pathogenesis of AD. In humans and mice, the APP genes are predominantly expressed in neural tissues, and there is little evidence for expression in cell types other than neurons or ganglia (Goldgaber et al, 1987;Tanzi et al, 1987;Arai et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

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Tol2 gene trap integrations in the zebrafish amyloid precursor protein genes appa and aplp2 reveal accumulation of secreted APP at the embryonic veins

Liao

Wang

Watt

et al. 2012

Developmental Dynamics

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Background-The single spanning transmembrane amyloid precursor protein (APP) and its proteolytic product, amyloid-beta (Aβ) peptide, have been intensely studied due to their role in the pathogenesis of Alzheimer's disease. However, the biological role of the secreted ectodomain of APP, which is also generated by proteolytic cleavage, is less well understood. Here, we report Tol2 red fluorescent protein (RFP) transposon gene trap integrations in the zebrafish amyloid precursor protein a (appa) and amyloid precursor-like protein 2 (aplp2) genes. The transposon integrations are predicted to disrupt the appa and aplp2 genes to primarily produce secreted

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Section: Secreted Appa-and Aplp2-rfp Fusion Proteins Accumulate At Thsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Tol2 gene trap integrations in the zebrafish amyloid precursor protein genes appa and aplp2 reveal accumulation of secreted APP at the embryonic veins

Liao

Wang

Watt

et al. 2012

Developmental Dynamics

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“…The methods for tissue processing and light microscopic immunohistochemical analysis have been described (7,14,15,24). The antibodies used for immunohistochemistry included those described above to tau and A68, as well as a monoclonal antibody (mAb) to ubiquitin (mAb5lO1, Sigma), six different mAbs and polyclonal antisera to (BA4 (UP107, 2332, 1280, 2,84, AMY33, lOD5), and antibodies to non-,BA4 domains in the f3APPs (LN21 and LN27, which bind to epitopes within the first 200 residues of the 3APPs; anti-C15, which binds to the last 15 residues in the ,BAPPs).…”

Section: Methodsmentioning

confidence: 99%

Alzheimer disease A68 proteins injected into rat brain induce codeposits of beta-amyloid, ubiquitin, and alpha 1-antichymotrypsin.

Shin

Bramblett

Lee

et al. 1993

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

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Aberrandy phosphorylated tau proteins (i.e., A68 or PHF-tau) and (-amyloid MATERIALS AND METHODS Isolation and Characterization of A68, Dephosphorylated A68 (DEP-A68), and Normal Tau. A68 was purified from the brains of four AD patients and one Down syndrome patient with . To render A68 water soluble for injection, A68 was further purified as follows. After sucrose gradient centrifugation (14,15), the 1.25-2.0 M and 2.25-2.5 M sucrose fractions were extracted in 2 M guanidine isothiocyanate at 37°C for 60 min, and the guanidine-insoluble material was removed by further centrifugation for 30 min at 100,000 x g. The supernatant was exhaustively dialyzed against distilled water, and the water-insoluble material was removed by centrifugation once again. The resulting supernatant was lyophilized and used for injection into rats as well as for the generation of DEP-A68. This guanidine-extracted, water-soluble supernatant was shown by Western blots (see below) to contain purified A68. Although the A68 preparation contained PHFs (14) prior to guanidine extraction, the guanidine-extracted, water-soluble A68 did not reassemble into PHFs or straight filaments in vitro (data not shown), as monitored by negative staining and electron microscopy (14). DEP-A68 was generated from A68 by enzymatic dephosphorylation after overnight incubation in type III-N Escherichia coli alkaline phosphatase (20 units/ml) at 37°C as described (14). Normal adult human tau was prepared exactly as described (14,15). Aliquots of the A68, DEP-A68, and normal adult human tau preparations that were used for injection were analyzed by gel electrophoresis and by Western blots with epitope-specific antibodies to A68 and tau according to described methods (2,3,14,15). The anti-tau and anti-A68 antibodies used in this study included Alz5O to residues 2-10; T60 to residues 119-150; T14 to residues 141-178; T46 to residues 404-441; Taul, which recognizes tau and DEP-A68, but not A68, and binds to a nonphosphorylated epitope within residues 189-207; T3P, which recognizes A68, but not tau or DEP-A68, and binds to an epitope within residues 389-402 that contains a phosphate at Ser-396; and PHF1, which is similar to the T3P antiserum (for further information on these antibodies, see refs. 2, 3, and 14-21 and citations therein; the numbering system for the amino acids in tau referred to here is based on the largest tau isoform, as described in ref. 22

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“…(e-j) Neuronal GT1-7 cells stably transfected with SYN cDNA (e-g) or control plasmid (h-j) as described (27), were left untreated (e and h) or exposed for 48 h to A␤1-40 ( f and i), A␤1-42 (g and j), or A␤42-1 (not shown) at 2 M final concentration, followed by immunoperoxidase staining with anti-SYN (27). (47)(48)(49). Our study demonstrates that hSYN and hAPP͞A␤ have distinct, as well as convergent, pathogenic effects on the integrity and function of the brain.…”

Section: A␤ Promotes Accumulation Of Hsynmentioning

confidence: 99%

β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease

Masliah

Rockenstein

Veinbergs

et al. 2001

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

570

466

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Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of ␤-amyloid and ␣-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human ␤-amyloid peptides, ␣-synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before ␣-synuclein singly tg mice, and showed prominent agedependent degeneration of cholinergic neurons and presynaptic terminals. They also had more ␣-synuclein-immunoreactive neuronal inclusions than ␣-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in ␣-synuclein singly tg mice. ␤-Amyloid peptides promoted aggregation of ␣-synuclein in a cell-free system and intraneuronal accumulation of ␣-synuclein in cell culture. ␤-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of ␣-synuclein and exacerbating ␣-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of ␤-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.A ging is a major risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and the number of people with these conditions is increasing rapidly. In the United States alone, an estimated 4 million people have AD and at least one million have PD. Within the next 40-50 years, these numbers are projected to increase to over 8 million for AD and to 4 million for PD. Each neurodegenerative disease appears to have a predilection for specific brain regions and cell populations. However, human cases with clinical and neuropathological features of both AD and PD (1-3) raise the possibility that these diseases involve overlapping pathways.Many AD patients develop signs of PD and some PD patients become demented (3). Both diseases are associated with degeneration of neurons and interneuronal synaptic connections, depletion of specific neurotransmitters, and abnormal accumulation of misfolded proteins, whose precursors participate in normal central nervous system functions (4-11). The ␤-amyloid protein precursor (APP) and ␣-synuclein (SYN) are expressed abundantly in synapses, are well conserved across species, and have been implicated in neural plasticity, learning, and memory (6,7,12). Mutations in human APP (hAPP) that increase production of hAPP-derived ␤-amyloid peptides (A␤) cause autosomal dominant forms of familial AD (FAD) (11), and expression of FAD-mutant hAPPs in neurons of transgenic (tg) mice results in the age-dependent development of AD-like central nervous system alterations (13-17). Mutations in human SYN (hSYN) that enhance hSYN aggregation have bee...

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Expression patterns of β‐amyloid precursor protein (β‐APP) in neural and nonneural human tissues from alzheimer's disease and control subjects

Cited by 151 publications

References 31 publications

Tol2 gene trap integrations in the zebrafish amyloid precursor protein genes appa and aplp2 reveal accumulation of secreted APP at the embryonic veins

Tol2 gene trap integrations in the zebrafish amyloid precursor protein genes appa and aplp2 reveal accumulation of secreted APP at the embryonic veins

Alzheimer disease A68 proteins injected into rat brain induce codeposits of beta-amyloid, ubiquitin, and alpha 1-antichymotrypsin.

β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease

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