Prion protein (PrPc) promotes β-amyloid plaque formation

Schwarze-Eicker, Katja; Keyvani, Kathy; Görtz, Nicole; Westaway, David; Sachser, Norbert; Paulus, Werner

doi:10.1016/j.neurobiolaging.2004.10.004

Cited by 81 publications

(48 citation statements)

References 30 publications

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“…For example an study of Debatin and coworkers reported the cooccurrence of pathological changes typical for sporadic CJD and Alzheimer´s disease in combination with the inverse association between accumulation of A and PrP sc in a subgroup of sporadic CJD patients as indicative of pathways involved in the generation or clearance of A and PrP sc in a subgroup of sporadic CJD patients (Debatin et al, 2008). This study was in contrast results obtained in mouse models were the inoculation with PrP sc increased A deposition in AD models (Baier et al, 2008) or studies reporting increased A accumulation in PrP c mutant models (Schwarze-Eicker et al, 2005). In a first study, Parkin and coworked determined that PrPc modulated BACE1 activity being a negative regulator of A production (Parkin et al, 2007).…”

Section: 4-emerging Roles Of Prp C Modulating A Deposition and Almentioning

confidence: 75%

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

Nicolas

Gavı́n

Rı́o

2009

Brain Research Reviews

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Section: 4-emerging Roles Of Prp C Modulating A Deposition and Almentioning

confidence: 75%

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

Nicolas

Gavı́n

Rı́o

2009

Brain Research Reviews

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“…It should be noted that increased levels of murine A␤ do not result in amyloid plaque deposition (16). A recent study reported that bigenic mice carrying mutant human APP and wild-type Syrian hamster PrP had increased amyloid plaques but no significant alteration in A␤ or A␤ 1-42 levels compared to control mice carrying just the mutant APP (17). Because these control mice have endogenous levels of murine PrP C , which may be maximally inhibiting the ␤-cleavage of APP (see Fig.…”

Section: Resultsmentioning

confidence: 99%

Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein

Parkin

Watt²,

Hussain³

et al. 2007

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

255

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Proteolytic processing of the amyloid precursor protein (APP) by ␤-secretase, ␤-site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid ␤ (A␤) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrP C ), the causative agent of the transmissible spongiform encephalopathies such as CreutzfeldtJakob disease in humans, remains enigmatic. Because both APP and PrP C are subject to proteolytic processing by the same zinc metalloproteases, we tested the involvement of PrP C in the proteolytic processing of APP. Cellular overexpression of PrP C inhibited the ␤-secretase cleavage of APP and reduced A␤ formation. Conversely, depletion of PrP C in mouse N2a cells by siRNA led to an increase in A␤ peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapieinfected mice, A␤ levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the ␤-secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrP C on the ␤-secretase cleavage of APP required the localization of PrP C to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrP C via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic A␤ is regulated by PrP C and may have implications for both Alzheimer's and prion diseases.lipid raft ͉ proteolysis ͉ scrapie ͉ glycosaminoglycan A lzheimer's disease (AD) is characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles within the afflicted brain. The major constituents of senile plaques are the amyloid ␤ (A␤) peptides, which are derived from the proteolytic processing of the amyloid precursor protein (APP) (1). In the amyloidogenic pathway, ␤-secretase cleavage of APP yields a soluble N-terminal fragment sAPP␤, along with a short membrane-bound C-terminal fragment that is subsequently cleaved by ␥-secretase to release the A␤ peptides. In the alternative, nonamyloidogenic pathway, ␣-secretase cleaves APP within the A␤ sequence, thus precluding the formation of A␤, and releases a soluble N-terminal fragment sAPP␣. The transmembrane aspartyl protease, ␤-site APP cleaving enzyme (BACE1), has been identified as ␤-secretase (2), members of the ADAM (a disintegrin and metalloprotease) family, particularly ADAM10 and ADAM17, are responsible for ␣-secretase cleavage (3), while a complex of at least four proteins, the presenilins, nicastrin, Aph-1, and Pen-2, constitutes the ␥-secretase (2).The prion protein (PrP) is the causative agent of the transmissible spongiform encephalopathies (TSEs) that include CreutzfeldtJakob disease (CJD), Gerstmann-Scheinker-Straussler (GSS) disease, kuru and fatal familial insomnia in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep (4). In these diseases, the normal ce...

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“…In addition, Hooper and Turner described that PrP c inhibits BACE1-dependent APP cleavage (Hooper and Turner, 2008). In contrast, other authors have indicated that PrP c increases A deposition (Schwarze-Eicker et al, 2005) or that Aβ levels increase in an AD mouse model after prion inoculation (Baier et al, 2008). …”

Section: Discussionmentioning

confidence: 99%

Involvement of Dab1 in APP processing and β-amyloid deposition in sporadic Creutzfeldt–Jakob patients

Gavı́n¹,

Ferrer²,

Rı́o³

2010

Neurobiology of Disease

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Alzheimer's disease and prion pathologies (e.g., Creutzfeldt-Jakob disease (CJD)) display profound neural lesions associated with aberrant protein processing and extracellular amyloid deposits. Dab1 has been implicated in the regulation of Amyloid Precursor Protein (APP), but a direct link between human prion diseases and Dab1/APP interactions has not been published. Here we examined this putative relationship in seventeen cases of sporadic CJD (sCJD) post mortem. Biochemical analyses of brain tissue revealed two groups, which also correlated with PrP sc types 1 and 2. One group, with PrP sc type 1 showed increased Dab1 phosphorylation, and lower CTF production with an absence of A deposition. The second sCJD group, which carried PrP sc type 2, showed lower levels of Dab1 phosphorylation and CTF production, and A deposition. Thus, the present observations suggest a correlation between Dab1-phosphorylation, A deposition and PrP sc type in sCJD.

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Prion protein (PrPc) promotes β-amyloid plaque formation

Cited by 81 publications

References 30 publications

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein

Involvement of Dab1 in APP processing and β-amyloid deposition in sporadic Creutzfeldt–Jakob patients

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