Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models

Abstract

The deposition of neurotoxic amyloid-β (Aβ) peptides in extracellular plaques in the brain parenchyma is one of the most prominent neuropathological features of Alzheimer's disease (AD), and considered to be closely related to the pathogenesis of this disease. A number of recent studies demonstrate the heterogeneity in the composition of Aβ deposits in AD brains, due to the occurrence of elongated, truncated and post-translationally modified Aβ peptides that have peculiar characteristics in aggregation behavior and biostability. Importantly, the detection of modified Aβ species has been explored to characterize distinct stages of AD, with phosphorylated Aβ being present in the clinical phase of AD. People with Down syndrome (DS) develop AD pathology by 40 years of age likely due to the overproduction of Aβ caused by the additional copy of the gene encoding the amyloid precursor protein on chromosome 21. In the current study, we analysed the deposition of phosphorylated and non-phosphorylated Aβ species in human DS, AD, and control brains. In addition, deposition of these Aβ species was analysed in brains of a series of established transgenic AD mouse models using phosphorylation-state specific Aβ antibodies. Significant amounts of Aβ phosphorylated at serine residue 8 (pSer8Aβ) and unmodified Aβ were detected in the brains of DS and AD cases. The brains of different transgenic mouse models with either only human mutant amyloid precursor protein (APP), or combinations of human mutant APP, Presenilin (PS), and tau transgenes showed distinct agedependent and spatiotemporal deposition of pSer8Aβ in extracellular plaques and within the vasculature. Together, these results demonstrate the deposition of phosphorylated Aβ species in DS brains, further supporting the similarity of Aβ deposition in AD and DS. Thus, the detection of phosphorylated and other modified Aβ species could contribute to the understanding and dissection of the complexity in the age-related and spatiotemporal deposition of Aβ variants in AD and DS as well as in distinct mouse models.

TREM2 modulates differential deposition of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits

“…Notably, increased deposition of pSer8-Aβ and nmAβ was not only observed in form of extracellular plaques, but also in brain vessels of APP/PS1L166P-TREM2 -/- mice as compared to APP/PS1L166P-TREM2 +/+ mice (Additional file 1 : Figure S7e). This vascular deposition of Aβ resembles cerebral amyloid angiopathy (CAA) observed in different APP transgenic mouse models, and very commonly in human AD brains [ 11 , 37 , 65 ].

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Novel Phosphorylation-State Specific Antibodies Reveal Differential Deposition of Ser26 Phosphorylated Aβ Species in a Mouse Model of Alzheimer’s Disease

“…The accumulation of age-dependent post-translational modifications in Aβ may be contributing factors to aggregation and toxicity, and thus to the pathogenesis of AD (Thal et al, 2015 ; Barykin et al, 2017 ; Roher et al, 2017 ; Schaffert and Carter, 2020 ). Various modified Aβ species are detected in the brains of human AD patients, DS cases, transgenic AD mouse and natural animal species that develop Aβ related pathology (Saido et al, 1995 , 1996 ; Iwatsubo et al, 1996 ; Russo et al, 1997 ; Tekirian et al, 1998 ; Fonseca et al, 1999 ; Shimizu et al, 2000 ; Schilling et al, 2008 ; Wirths et al, 2010 ; Saito et al, 2011 ; Frost et al, 2013 ; Kumar et al, 2013 , 2016 , 2020 ). Some of the modified species are also observed intraneuronally, years before plaque development, NFT formation, and synaptic loss (Wirths et al, 2004 , 2010 ; Bayer and Wirths, 2010 ; Jawhar et al, 2011 ; Li et al, 2018 ).…”

“…Phosphorylation of Aβ alters its conformation, aggregation, stability, neurotoxicity, proteolytic degradation and deposition (Kumar et al, 2011 , 2012 ; Rijal Upadhaya et al, 2014 ; Ashby et al, 2015 ; Rezaei-Ghaleh et al, 2016a , b ). Immunohistochemical and immunofluorescence stainings demonstrated the occurrence of pSer8Aβ and pSer26Aβ in vivo in the brains of human AD patients (Rijal Upadhaya et al, 2014 ; Ashby et al, 2015 ; Gerth et al, 2018 ), DS cases (Kumar et al, 2020 ), non-human primates and canines (Kumar et al, 2018 ). Notably, the detection of pSer8Aβ, together with pyroglutamate modified Aβ in brain sections or brain homogenates has been recently explored to establish a staging system for AD pathology based on the sequential deposition of these modified Aβ variants during the pathogenesis of AD (Rijal Upadhaya et al, 2014 ; Thal et al, 2015 , 2019 ; Gerth et al, 2018 ).…”

“…By using phosphorylation-state specific monoclonal antibodies (mAbs), we showed that phosphorylated Ser8-Aβ (pSer8Aβ) accumulates early inside of brain neurons of transgenic APP/PS1 knock-in mice, and is also a prominent component of extracellular plaques during aging (Kumar et al, 2013 ). The presence of pSer8Aβ was also demonstrated in the brains of human sporadic AD, FAD, CAA, Down syndrome (DS) cases, non-human primates, canines, and a variety of transgenic mouse models (Kumar et al, 2011 , 2018 , 2020 ; Rijal Upadhaya et al, 2014 ; Ashby et al, 2015 ; Gerth et al, 2018 ). Aβ can also undergo phosphorylation at serine residue 26, which strongly affects its conformation, aggregation, neurotoxicity, and deposition (Milton, 2001 ; Kumar et al, 2016 ).…”

Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules

“…In DS subjects, aged > 40 years, levels of cortical Aβ deposition are similar to those seen in late onset AD and demonstrate cored neuritic plaques, which have high significance for neuropathological diagnostic purposes [ 29 , 36 , 44 , 45 , 46 ]. Remarkably, autoptic DS brain display the presence of isomerized, racemized, truncated, pyroglutamate, and oxidized Aβ, indicating its accumulation of different post-translational modified forms [ 47 ]. Moreover, trisomy of chromosome 21 results in increased gene dosage to many other genes beyond APP that may play a critical role in DS neuropathology.…”