Pyroglutamate-3 Amyloid-β Deposition in the Brains of Humans, Non-Human Primates, Canines, and Alzheimer Disease–Like Transgenic Mouse Models

Abstract

Amyloid-β (Aβ) peptides, starting with pyroglutamate at the third residue (pyroGlu-3 Aβ), are a major species deposited in the brain of Alzheimer disease (AD) patients. Recent studies suggest that this isoform shows higher toxicity and amyloidogenecity when compared to full-length Aβ peptides. Here, we report the first comprehensive and comparative IHC evaluation of pyroGlu-3 Aβ deposition in humans and animal models. PyroGlu-3 Aβ immunoreactivity (IR) is abundant in plaques and cerebral amyloid angiopathy of AD and Down syndrome patients, colocalizing with general Aβ IR. PyroGlu-3 Aβ is further present in two nontransgenic mammalian models of cerebral amyloidosis, Caribbean vervets, and beagle canines. In addition, pyroGlu-3 Aβ deposition was analyzed in 12 different AD-like transgenic mouse models. In contrast to humans, all transgenic models showed general Aβ deposition preceding pyroGlu-3 Aβ deposition. The findings varied greatly among the mouse models concerning age of onset and cortical brain region. In summary, pyroGlu-3 Aβ is a major species of β-amyloid deposited early in diffuse and focal plaques and cerebral amyloid angiopathy in humans and nonhuman primates, whereas it is deposited later in a subset of focal and vascular amyloid in AD-like transgenic mouse models. Given the proposed decisive role of pyroGlu-3 Aβ peptides for the development of human AD pathology, this study provides insights into the usage of animal models in AD studies.

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

“…Moreover, in AD patients a better correlation seems to exist between decline in Mini-Mental State Examination and elevated pE3-Ab, rather than load of deposits of unmodified Ab (Morawski et al, 2014). In contrast to humans, in many transgenic animal models pE3-Ab deposition often occurs later than general Ab deposition with the age of onset varying in different mouse models (Frost et al, 2013).…”

“…pE3-Ab has been reported to be a major component of b-amyloid plaques and vessel deposits in AD brains; it has also been suggested that pE3-Ab plays an early and seminal role in Ab oligomerization and aggregation due to its high aggregation propensity (Frost et al, 2013). Moreover, in AD patients a better correlation seems to exist between decline in Mini-Mental State Examination and elevated pE3-Ab, rather than load of deposits of unmodified Ab (Morawski et al, 2014).…”

Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer’s disease

“…This suggests that in the parenchyma, pyroglutamate Aβ-formation might represent a later step in plaque maturation which might depend on remodeling of existing extracellular deposits. The presence of pyroglutamate Aβ deposits in transgenic mouse models has been confirmed in a variety of studies demonstrating that pyroglutamate Aβ-immunoreactivity is mainly confined to the amyloid core [23, 33, 40, 55]. In order to verify the in vivo toxicity of pyroglutamate Aβ, mouse models expressing solely the respective peptide but not the entire human APP molecule have been developed.…”

Mitochondrial dysfunction induced by a post-translationally modified amyloid linked to a familial mutation in an alternative model of neurodegeneration

“…These modified forms of Aβ have been shown to be more neurotoxic than full-length, unmodified Aβ [25–28]. Accordingly, pE-containing Aβ is more abundant in the AD brain compared to healthy age-matched controls, suggesting an important role of this modification in the pathogenesis of this disease [29–33]. …”