Koutarapu S, Ge J, Dulewicz M, Srikrishna M, Szadziewska A, Wood J, Blennow K, Zetterberg H, Michno W, Ryan NS, Lashley T, Savas JN, Schöll M, Hanrieder J. Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer's disease spectrum. Nat Commun. 2025 Apr 24;16(1):3889. PubMed.
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Katholieke Universiteit Leuven, Department of Imaging and Pathology, Laboratory of Neuropathology
Koutarapu et al. used mass spectrometry imaging and deep-learning strategies for image analysis to distinguish diffuse plaques from cored and coarse-grained plaques on “unbiased” morphological and biochemical grounds. For this classification, the deep-learning algorithm used not only the morphological appearance but also the abundance of distinct Aβ proteoforms such as Aβ40, Aβ42, and post-translationally modified Aβ species such as AβN3pE, and AβN11pE. In this context, dense-core plaques more frequently exhibited AβN3pE-42 and AβN11pE-42 than did diffuse plaques and were more associated with symptomatic Alzheimer’s disease (AD) compared to diffuse plaques. The coarse-grained plaque associated with a higher neuritic component and with familial AD. Dense-core plaques in cognitively unimpaired amyloid-positive individuals also exhibited AβN3pE-42, and AβN11pE-42.
With these findings the authors introduced a valuable new method to the field, namely mass spectrometry imaging coupled with deep-learning image analysis, that may help to learn more about neuropathological aggregates, such as Aβ plaques. Here, they used this method to confirm and extend earlier studies on the deposition of distinct Aβ species in amyloid plaque types and during the evolution of AD neuropathological changes throughout the pathogenesis of AD, from asymptomatic into symptomatic stages (Iwatsubo et al., 1994; Iwatsubo et al., 1996; Lemere et al., 1996; Saido et al., 1995). Most importantly, the critical role of AβN3pE-42, and AβN11pE-42 was confirmed, as well as their position as a second step in amyloid plaque/amyloid pathology formation after deposition of non-pyroglutamate modified Aβ species (Lemere et al., 1996; Rijal Upadhaya et al., 2014). By doing so, the authors shed strong light on the role of proteoforms of Aβ and their contribution to disease development.
Accordingly, evidence is provided by Koutarapu et al., as well as by earlier studies, that proteoforms of Aβ not only play an important role in the determination of the morphological appearance of plaques but also contribute to the maturation process of Aβ aggregates. Proteoforms make aggregates more stable and more prone to induce synaptic changes, as can be seen in APP23 mice, which have AβN3pE deposits at 11 months and develop a loss of asymmetric synapses at 15 months (Balakrishnan et al., 2015; Rijal Upadhaya et al., 2012). Therefore, we need to further clarify the impact of post-translational modifications in AD-relevant proteins and their potential to modify the aggregation behavior and toxicity of protein aggregates in neurodegenerative diseases. Mass spectrometry imaging has the potential to become an important tool for such questions.
References:
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