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 age-dependent 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.
Highlights
Depositions of amyloid-β (Aβ) peptides as senile plaques in the brain parenchyma and in the walls of cerebral blood vessels are common neuropathological features of the Alzheimer’s disease (AD) [1,2,3]
Additional heterogeneity in Aβ peptides comes from a number of post-translational modifications that are found in characteristic Aβ deposits in parenchymal extracellular plaques and cerebral amyloid angiopathy (CAA) [14,15,16,17,18,19,20,21,22]
Human hippocampal brain sections were stained with monoclonal antibodies recognizing the Nterminus of Aβ starting at amino acid Asp1 (Aβ1-x) (Fig. 1a, d and g), with monoclonal antibodies recognizing Aβ with Ser8 in phosphorylated (Fig. 1c, f and i, supplementary Fig. 1) or nonphosphorylated state (Fig. 1b, e and h, supplementary Fig. 1) to assess Aβ deposition in 3 Down syndrome (DS), 12 AD and 8 aged control (AC) brains
Summary
Depositions of amyloid-β (Aβ) peptides as senile plaques in the brain parenchyma and in the walls of cerebral blood vessels are common neuropathological features of the Alzheimer’s disease (AD) [1,2,3]. In addition to the generation and deposition of wellcharacterized Aβ40 and Aβ42 amino acid length variants, recent studies showed the occurrence of several Nand C-terminally truncated or elongated Aβ species that result from alterations in the cleavage by β- and γ-secretase or alternative processing by other proteases [7,8,9,10,11,12,13]. In DS subjects, aged > 40 years, levels of cortical Aβ deposition are similar to those observed in sporadic, late onset AD and demonstrate cored neuritic plaques, which are of neuropathological diagnostic significance in AD [29,30,31].Notably, autopsy studies of DS brain show the occurrence of isomerized, racemized, truncated, pyroglutamate and oxidized Aβ, indicating the accumulation of post-translationally modified Aβ variants as reviewed previously [30]
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