Identification of Amino-Terminally and Phosphotyrosine-Modified Carboxy-Terminal Fragments of the Amyloid Precursor Protein in Alzheimer's Disease and Down's Syndrome Brain

Russo, Claudio; Salis, Serena; Dolcini, Virginia; Venezia, Valentina; Song, Xiang-Hong; Teller, Jan K.; Schettini, Gennaro

doi:10.1006/nbdi.2001.0419

Cited by 29 publications

(51 citation statements)

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“…A rapid cleavage of CTFs to Aβ in soluble pools, which were not measured in this study, or intact CTF clearance mechanisms in normal aging may account for this result. In DS, we observed age-dependent increases in beta-secretase activity that were consistent with an increase in CTF-beta, similar to previous reports [41,53]. These results suggest that in DS, increased CTF-beta levels more closely parallel reports in AD cases [69] rather than that observed in normal aging.…”

Section: Discussionsupporting

confidence: 90%

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Nistor

Don

Parekh

et al. 2007

Neurobiology of Aging

110

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Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alphasecretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Aβ) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Aβ degradation and clearance.

show abstract

Section: Discussionsupporting

confidence: 90%

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Nistor

Don

Parekh

et al. 2007

Neurobiology of Aging

110

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“…1), phosphorylation of the APP CTFs could interfere with their interaction with Fe65 and diminish the stability of AICD. The C terminus of APP can be phosphorylated at multiple sites, including threonine 654, serine 655, threonine 668 (Oishi et al, 1997), and tyrosine 682 (Russo et al, 2001). Although there is evidence that phosphorylation occurs at each of these sites in various cell lines, we were particularly interested in T668, because this phosphorylation event is neuron specific (Iijima et al, 2000) and because it is the only such modification that has been shown to cause a neuronal phenotype: a defect in neurite extension (Ando et al, 1999).…”

Section: Resultsmentioning

confidence: 99%

Physiological Regulation of the -Amyloid Precursor Protein Signaling Domain by c-Jun N-Terminal Kinase JNK3 during Neuronal Differentiation

Kimberly

Zheng²,

Town³

et al. 2005

Journal of Neuroscience

108

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␤-Amyloid precursor protein (APP) is a conserved and ubiquitous transmembrane glycoprotein strongly implicated in the pathogenesis of Alzheimer's disease but whose normal biological function is unknown. Analogy to the Notch protein suggests that APP is a cell-surface receptor that signals via sequential proteolytic cleavages that release its intracellular domain (AICD) to the nucleus. Because these cleavages are major targets for therapeutic inhibition, it is critical to elucidate their physiological function. AICD is stabilized by Fe65, interacts with the transcriptional factor Tip60, and translocates to the nucleus. Here, we show that endogenous AICD in primary neurons is detectable only during a short period of time during differentiation in culture. During this transient rise, a portion of AICD localizes to the nucleus. Subsequently, phosphorylation of the APP cytoplasmic domain at threonine 668 appears to disrupt the stabilizing interaction with Fe65 and thus downregulate AICD-mediated signaling. Furthermore, we find that the neuron-specific c-Jun N-terminal kinase JNK3, but not JNK1 or JNK2, mediates a substantial portion of this phosphorylation. We conclude that endogenous AICD undergoes tight temporal regulation during the differentiation of neurons and is negatively regulated by JNK3 via phosphorylation of APP at Thr668.

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“…A growing body of evidence, albeit indirect, suggests the involvement of CTFs in AD-related pathogenesis. CTFs have been detected in tangle-bearing neurons in the AD brain (Lahiri et al, 2002), in dystrophic neurites around senile plaques (Shoji et al, 1990), and in the Down's syndrome brain (Russo et al, 2001). In cultured neuronal cells, various forms of CTFs, for examples, CTF31, AICD (CTF57 and CTF59), and hCTF99, can exert neurotoxicity, which is associated with the induction of glycogen synthase kinase 3h or with the inhibition of histone deacetylation (Kim et al, 2003.…”

Section: The Roles Of Bctf99 In Ad-related Pathogenesismentioning

confidence: 99%

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

Lee

Song

et al. 2006

Neurobiology of Disease

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Identification of Amino-Terminally and Phosphotyrosine-Modified Carboxy-Terminal Fragments of the Amyloid Precursor Protein in Alzheimer's Disease and Down's Syndrome Brain

Cited by 29 publications

References 0 publications

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Physiological Regulation of the -Amyloid Precursor Protein Signaling Domain by c-Jun N-Terminal Kinase JNK3 during Neuronal Differentiation

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

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