Amyloid Maturation Patterns in Alzheimer's Disease - Novel chemical imaging of Aβ and Tau pathology

Abstract

Alzheimer’s disease (AD) accounts for approximately 70% of dementia cases in Sweden. It can be of genetic origin i.e. familial form (fAD), sporadic form (sAD). AD is characterized by the deposition of amyloid and tau proteins in abnormal amounts leading to the development of two pathological hallmarks extracellular amyloid beta (Aβ) plaques, and intracellular neurofibrillary tangles (NFTs) consisting of tau protein. AD is sometimes also associated with amyloid-deposited blood vessels, a condition referred to as cerebral amyloid angiopathy (CAA). Interestingly, Aβ plaques can also be found in individuals without cognitive impairment, known as Cognitively Unaffected Amyloid Positive (CU-AP) individuals. Amyloid depositions vary in terms of their size, shape, composition, distribution, and how they influence their surroundings. This thesis interrogated the molecular architecture of heterogeneous AD pathology by leveraging highly advanced imaging techniques like light microscopy and mass spectrometry imaging (MSI). In light microscopy, we performed immunohistochemistry (IHC) using unique fluorophores known as Luminescent Conjugated Oligothiophenes (LCOs with antibodies targeting phosphorylated tau protein (pTau). This innovative imaging approach allowed us to investigate the interactions between Aβ plaques and their microenvironment, specifically their association with neuronal lipids, in mouse models. Additionally, we delved into the study of CAA in non-AD conditions such as familial British Dementia and familial Danish Dementia. We identified and examined the biochemical profiles of distinct Aβ plaque types, including diffuse plaques, cored plaques, cotton wool plaques, and notably, the newly identified coarse grain plaques. For the first time, we unveiled the chemical distinctions of neuritic cored plaques and non-neuritic cored plaques. These neuritic components consist of paired helical filaments, a fundamental element in the formation of NFTs. NFTs develop within neurons and undergo a developmental progression. To investigate NFT pathology, we leveraged hyperspectral imaging techniques using confocal microscopy. Hyperspectral analysis of NFTs using LCOs revealed distinct emission profiles at various maturation stages. Additionally, an examination of NFTs uncovered a process known as axonal sorting of tau within neurons. We expanded our investigation by assessing the binding capacity of an unmodified (cold) tau tracer molecule called GTP1. We conducted IHC on brain sections of individuals diagnosed with sAD, utilizing GTP1, LCO, and pTau antibodies. This combined analysis strengthens our ability to cover a broad spectrum of structurally distinct tau deposits. In conclusion, AD, with its diverse pathological characteristics, presents a complex puzzle for researchers. The recent approval of lecanemab, a monoclonal antibody designed to reduce the plaque load in AD-diagnosed individuals underscores the importance of understanding the chemical processes underlying the formation of Aβ plaques. Furthermore, emerging evidence suggests cognitive decline is primarily influenced by the interplay between Aβ and tau, rather than the contribution of Aβ or tau alone. Consequently, it is crucial to conduct thorough investigations to fully understand the roles played by both Aβ plaques and NFTs in the context of Alzheimer's disease. This multifaceted approach shows promise in contributing to the development of more effective prognostic and diagnostic criteria for AD.