Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease

Abstract

Pyroglutamate-modified amyloid-␤ (A␤ pE3 ) peptides are gaining considerable attention as potential key participants in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Transgenic mice that produce high levels of A␤ pE3-42 show severe neuron loss. Recent in vitro and in vivo experiments have proven that the enzyme glutaminyl cyclase catalyzes the formation of A␤ pE3 . In this minireview, we summarize the current knowledge on A␤ pE3 , discussing its discovery, biochemical properties, molecular events determining formation, prevalence in the brains of AD patients, Alzheimer mouse models, and potential as a target for therapy and as a diagnostic marker.When Alois Alzheimer presented the case of his patient Auguste Deter at the Tübingen meeting of the Southwest German Psychiatrists in 1906, he did not attract much attention or stimulate any discussion in the audience. The young doctor likely would not have believed that, 100 years later, the disease that now holds his name would be the most common cause of dementia and a source of a critical medical and economical problem. At this meeting, Alzheimer presented Auguste Deter's symptoms and reported the histopathological features that are now associated with Alzheimer disease (AD) 2 : neuron loss, extracellular amyloid plaques, and intracellular neurofibrillary tangles. For more than 2 decades, the amyloid hypothesis has been the cardinal hypothesis in describing the sequence of AD etiology. The amyloid hypothesis considers amyloid-␤ (A␤) deposition to be the causative event of AD pathology and that neurofibrillary tangles, cell loss, vascular damage, and dementia occur as a consequence of it (1). However, it has been recently suggested that the extracellular formation of A␤ plaques and other AD pathological events are preceded by intraneuronal A␤ accumulation, giving rise to a modified amyloid hypothesis (2).The story of successful discoveries in modern AD research using novel molecular biological tools started with the biochemical analysis of ␤-amyloid-containing blood vessels (congophilic amyloid angiopathy) (3) and amyloid plaques consisting of A␤ (4), which led to the isolation and sequencing of the gene encoding the larger amyloid precursor protein (APP) (5, 6).In vitro and in vivo analyses of amyloid deposits in AD revealed various N-and C-terminal variants (4, 7, 8). Increased C-terminal length of A␤ (from A␤ x-40 to A␤ x-42 ) in AD enhanced aggregation and early deposition and promoted the toxicity of A␤ (9 -11). Recently, A␤ 1-43 has been discussed as a novel toxic peptide in AD (12).Beside A␤ peptides, starting with aspartate as the first amino acid (A␤ 1-x ), several N-terminally truncated and modified A␤ species have been described (4, 13-15). Among A␤ species present in AD plaques, Lewis et al. (16) reported that A␤ 4 -42 is a relatively abundant species in AD, aged control, and vascular dementia patients. Using immunoprecipitation in combination with mass spectrome...

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

“…A␤ pE3 isoforms have been identified by several groups in AD brains (12,13,15,36,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52). N-terminal deletions generally enhance aggregation of ␤-amyloid peptides in vitro (53).…”

Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates

“…These shortened pyroglutamylated peptides are reported to be more neurotoxic and to aggregate more rapidly than the full-length isoforms and to seed further Aß aggregation (He and Barrow, 1999;Nussbaum et al, 2012;Schilling et al, 2008). It is unclear whether pE3-Aß is present in early plaque deposits or it accrue later, and some authors have proposed that pyroglutamylated-Aß (pE-Aß) (40/42) peptides could be initiators of AD pathogenesis and others report that Aß4-42 precedes pE3-Aß (Antonios et al, 2013;Jawhar et al, 2011a;Schilling et al, 2008;Wirths et al, 2010).…”

CuII Binding to Various Forms of Amyloid‐β Peptides: Are They Friends or Foes?

“…[116,117] These peptides are considered to be more toxic than the full-length ones, [118][119][120][121][122][123][124][125][126][127][128][129][130][131] given their connection to modified plaque morphology, hampered degradation of the pyroglutamate forms, higher propensity to form -sheets, and impact on the process of aggregation of the full-length peptides. The formation of pyroglutamate at the 11-position (see above) is also possible, but its effect has been less studied.…”