title: Pyroglutamylated amyloid-β is associated with hyperphosphorylated tau and severity of Alzheimer's disease.
abstract: Pyroglutamylated amyloid-β (pE(3)-Aβ) has been suggested to play a major role in Alzheimer's disease (AD) pathogenesis as amyloid-β (Aβ) oligomers containing pE(3)-Aβ might initiate tau-dependent cytotoxicity. We aimed to further elucidate the associations among pE(3)-Aβ, full-length Aβ and hyperphosphorylated tau (HP-τ) in human brain tissue. We examined 41 post mortem brains of both AD (n = 18) and controls. Sections from frontal and entorhinal cortices were stained with pE(3)-Aβ, HP-τ and full-length Aβ antibodies. The respective loads were assessed using image analysis and western blot analysis was performed in a subset of cases. All loads were significantly higher in AD, but when using Aβ loads as independent variables only frontal pE(3)-Aβ load predicted AD. In frontal and entorhinal cortices pE(3)-Aβ load independently predicted HP-τ load while non-pE(3)-Aβ failed to do so. All loads correlated with the severity of AD neuropathology. However, partial correlation analysis revealed respective correlations in the frontal cortex only for pE(3)-Aβ load only while in the entorhinal cortex respective correlations were seen for both HP-τ and non-pE(3)-Aβ loads. Mini Mental State Examination scores were independently predicted by entorhinal HP-τ load and by frontal pE(3)-Aβ load. Here, we report an association between pE(3)-Aβ and HP-τ in human brain tissue and an influence of frontal pE(3)-Aβ on both the severity of AD neuropathology and clinical dementia. Our findings further support the notion that pE(3)-Aβ may represent an important link between Aβ and HP-τ, and investigations into its role as diagnostic and therapeutic target in AD are warranted.
authors.affiliation: AFFiRiS AG, Vienna Biocenter, Karl-Farkas-Gasse 22, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Mandler
authors.forename: Lauren
authors.initials: L
authors.lastname: Walker
authors.forename: Radmila
authors.initials: R
authors.lastname: Santic
authors.forename: Peter
authors.initials: P
authors.lastname: Hanson
authors.forename: Ajeet Rijal
authors.initials: AR
authors.lastname: Upadhaya
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Colloby
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Morris
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Thomas
authors.forename: Achim
authors.initials: A
authors.lastname: Schneeberger
authors.forename: Johannes
authors.initials: J
authors.lastname: Attems
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D018728:Entorhinal Cortex / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D010784:Photomicrography; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; D010446:Peptide Fragments; C532271:amyloid beta-protein (3-42), pyroglutamyl(3)-; D016875:tau Proteins