Amino- and carboxyl-terminal heterogeneity of β-amyloid peptides deposited in human brain

Section: Discussionmentioning

confidence: 99%

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

Wittnam

Portelius

Zetterberg

et al. 2012

“…Saido et al (45) suggested that A␤ pE3 and other modified A␤ species accumulate because of their limited degradation. The formation of the lactam ring and the loss of two negative charges and one positive charge result in higher hydrophobicity and thus more stability and aggregation propensity of the A␤ pE3-x peptides (45). In addition, the formation of the N-terminal pyroglutamate, which is resistant to degradation by peptidases, increases the stability of the peptide.…”

Section: Biochemical Properties Of Pyroglutamate A␤mentioning

confidence: 99%

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

Jawhar

Wirths

Bayer

2011

199

225

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...

“…An additional member of this group of enzymes is neutral endopeptidase, which recently was identified as a major A␤1-42-catabolizing enzyme (73 (75). The latter two amino-terminal-truncated A␤ peptide species are deposited before A␤ peptides 1-x and represent a dominant species in early stages of ␤-amyloid plaque formation (76,77).…”

Section: Amino-terminal-and Carboxyl-terminal-truncated A␤ Species Inmentioning

confidence: 99%

Elevation of β-Amyloid Peptide 2–42 in Sporadic and Familial Alzheimer's Disease and Its Generation in PS1 Knockout Cells

Wiltfang¹,

Esselmann²,

Cupers³

et al. 2001

120

123

show a decrease of all secreted A␤ peptide species, as expected, because this mutant is processed mainly by ␣-secretase. This drop is even more pronounced for the APP-KK construct (APP mutant carrying an endoplasmic reticulum retention motif). Surprisingly, A␤2-42 is significantly less affected in PS1؊/؊ neurons and in neurons transfected with the endocytosis-deficient APP-⌬ct construct. Our data confirm that PS1 is closely involved in the production of A␤1-40/42 and the carboxyl-terminal-truncated A␤1-37, A␤1-38, and A␤1-39, but the amino-terminaltruncated and carboxyl-terminal-elongated A␤2-42 seems to be less affected by PS1 deficiency. Moreover, our results indicate that the latter A␤ peptide species could be generated by a ␤ Asp/Ala -secretase activity.