Distinct deposition of amyloid-β species in brains with Alzheimer’s disease pathology visualized with MALDI imaging mass spectrometry

Abstract

Amyloid β (Aβ) deposition in the brain is an early and invariable feature of Alzheimer’s disease (AD). The Aβ peptides are composed of about 40 amino acids and are generated from amyloid precursor proteins (APP), by β- and γ-secretases. The distribution of individual Aβ peptides in the brains of aged people, and those suffering from AD and cerebral amyloid angiopathy (CAA), is not fully characterized. We employed the matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) to illustrate the spatial distribution of a broad range of Aβ species in human autopsied brains. With technical advancements such as formic acid pretreatment of frozen autopsied brain samples, we have: i) demonstrated that Aβ1–42 and Aβ1–43 were selectively deposited in senile plaques while full-length Aβ peptides such as Aβ1–36, 1–37, 1–38, 1–39, 1–40, and Aβ1–41 were deposited in leptomeningeal blood vessels. ii) Visualized distinct depositions of N-terminal truncated Aβ40 and Aβ42, including pyroglutamate modified at Glu-3 (N3pE), only with IMS for the first time. iii) Demonstrated that one single amino acid alteration at the C-terminus between Aβ1–42 and Aβ1–41 results in profound changes in their distribution pattern. In vitro, this can be attributed to the difference in the self-aggregation ability amongst Aβ1–40, Aβ1–41, and Aβ1–42. These observations were further confirmed with immunohistochemistry (IHC), using the newly developed anti-Aβ1–41 antibody. Here, distinct depositions of truncated and/or modified C- and N-terminal fragments of Aβs in AD and CAA brains with MALDI-IMS were visualized in a spacio-temporal specific manner. Specifically, Aβ1–41 was detected both with MALDI-IMS and IHC suggesting that a single amino acid alteration at the C-terminus of Aβ results in drastic distribution changes. These results suggest that MALDI-IMS could be used as a standard approach in combination with clinical, genetic, and pathological observations in understanding the pathology of AD and CAA.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0477-x) contains supplementary material, which is available to authorized users.

Current state of Alzheimer’s fluid biomarkers

“…The cleavage position of the γ-secretase in the transmembrane domain of APP is imprecise, resulting in the production of Aβ peptides of variable length [166, 289]. Changes in some of these Aβ species have been associated with AD, as discussed below, but little is known about the changes over time in relation to clinical presentation.…”

Chemical imaging of evolving amyloid plaque pathology and associated Aβ peptide aggregation in a transgenic mouse model of Alzheimer’s disease

“…In particular, matrix‐assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is a powerful, emerging technology for comprehensively delineating lipid, peptide and protein localizations in situ, while maintaining high chemical specificity (Hanrieder et al ; Hanrieder et al ; Michno et al ). In the context of AD, MALDI IMS has been demonstrated to be a powerful tool to measure Aβ peptide pattern in situ at single plaque resolution (Rohner et al ; Stoeckli et al ; Seeley and Caprioli ; Carlred et al ; Kaya et al ; Kakuda et al ; Michno et al ; Michno et al ; Michno et al ).…”

Whole brain optoacoustic tomography reveals strain-specific regional beta-amyloid densities in Alzheimer’s disease amyloidosis models

“…Initial cleavage of APP by β-secretase generates a membrane-bound C-terminal fragment of APP (β-CTF), which is sequentially processed by γ-secretase resulting in the formation of longer species, like Aβ40 and Aβ42/43, in addition to several other C-terminally truncated Aβ variants 58 . A full set of Aβ isoforms with both N- and C-terminally truncated Aβ species can be detected in the post-mortem AD brain and cerebrospinal fluid 59 . N-terminally truncated Aβ isoforms show an increased aggregation propensity and have previously been associated with the deposition of dense-core amyloid plaques in the brain 60 .…”