Morphological and Molecular Profiling of Amyloid-β Species in Alzheimer's Pathogenesis

Abstract

Alzheimer's disease (AD) is the most common form of dementia around the world (~ 65%). Here, we portray the neuropathology of AD, biomarkers, and classification of amyloid plaques (diffuse, non-cored, dense core, compact). Tau pathology and its involvement with Aβ plaques and cell death are discussed. Amyloid cascade hypotheses, aggregation mechanisms, and molecular species formed in vitro and in vivo (on- and off-pathways) are described. Aβ42/Aβ40 monomers, dimers, trimers, Aβ-derived diffusible ligands, globulomers, dodecamers, amylospheroids, amorphous aggregates, protofibrils, fibrils, and plaques are characterized (structure, size, morphology, solubility, toxicity, mechanistic steps). An update on AD-approved drugs by regulatory agencies, along with new Aβ-based therapies, is presented. Beyond prescribing Aβ plaque disruptors, cholinergic agonists, or NMDA receptor antagonists, other therapeutic strategies (RNAi, glutaminyl cyclase inhibitors, monoclonal antibodies, secretase modulators, Aβ aggregation inhibitors, and anti-amyloid vaccines) are already under clinical trials. New drug discovery approaches based on "designed multiple ligands", "hybrid molecules", or "multitarget-directed ligands" are also being put forward and may contribute to tackling this highly debilitating and fatal form of human dementia.

Keywords: Alzheimer’s disease (AD); Amyloid plaques; Amyloid-beta (Aβ) peptide; Aβ-based therapies; Protein aggregation; Tau protein.

Fig. 1

Domains and isoforms of the Tau protein. A Tau consists of 4 primary domains/regions: the N-terminal domain (red), the proline-rich domain (green), the repeat domain (RD) or microtubule-binding domain (blue), and the C-terminal region (gray). The CNS isoform hTau40, which is the longest one, consists of 441 amino acids and includes regions N1 and N2, as well as R1, R2, R3, and R4 (2N4R). RD is responsible for the formation of Tau filaments, working as a structural backbone. B Models for the formation of β-sheet-structures often employ Tau-based peptide fragments. The K18 fragment presents the R1-R2-R3-R4 domain, while the K19 fragment presents the R1-R3-R4 domain. Assembly of β-sheets is facilitated by the hexapeptides PHF6 and PHF6*. C Tau isoforms with lengths of 352 to 441 amino acids. Alternative splicing of the sub-domains N1, N2, and R2 results in the production of six isoforms within the CNS. The repeat domains R1, R3, and R4 are consistently present, while R2 is exclusively included in the three 4R isoforms. Skipping of N1 and/or N2 can occur, though the inclusion of N2 necessitates the inclusion of N1 as well. Consequently, the resultant variants encompass 0N3R (hTau23), 1N3R (hTau37), 2N3R (hTau39), 0N4R (hTau24), 1N4R (hTau34), and 2N4R (hTau40) Tau isoforms. Adapted from references [12, 13]

Fig. 2

Schematic representation of the formation of neurofibrillary tangles (NFTs) by the Tau protein in Alzheimer’s disease. In a non-amyloidogenic pathway, functional Tau is believed to play a role in the stabilization of axonal microtubules in neurons. However, under pathological conditions (amyloidogenic pathway), Tau becomes hyperphosphorylated and disconnects from microtubules. Phosphorylated Tau then aggregates via a nucleation-dependent mechanism (sigmoidal dash line) forming paired helical filaments (PHFs) and then NFTs that further lead to neuronal death. Adapted from reference [32]

Fig. 3

Spatiotemporal pattern of NFTs deposition during the AD disease cascade in the human brain according to Braak stages and “B” score. In Braak stages I–II, modifications primarily occur within the superficial layers of the transentorhinal cortex (referred to as transentorhinal stages). Braak stages III–IV exhibit extensive involvement of both the transentorhinal and entorhinal regions, with comparatively milder engagement of the hippocampus and various subcortical nuclei (designated as limbic stages). Braak stages V–VI show profound neurofibrillary pathology development within neocortical association areas (known as isocortical stages), along with a progressive escalation of pathology within brain regions affected during stages I–IV. Accordingly, Braak stages I–II, III–IV, and V–VI are scored as B1, B2, and B3, respectively. Stage B0 depicts no symptoms. Light red areas represent the regions affected by NFT deposition for each stage of neuropathology. Adapted from references [39, 44, 45]

Fig. 4

Amyloid precursor protein (APP) processing by secretase enzymes according to two different hydrolysis pathways. The non-amyloidogenic pathway shows a normal cleavage of APP by γ- and α-secretase, which leads to the release of the APP intracellular domain (AICD) and P3. The amyloidogenic pathway involves the cleavage of APP by the β-secretase enzyme to form β-CTF (or C99) and sAPPβ. Then, γ-secretase cleaves the resulting β-CTF, releasing the AICD and Aβ. Aβ monomers can assemble via a nucleation-dependent mechanism (sigmoidal dash line) to form higher-order structures, from oligomers to protofibrils, and eventually mature fibrils containing β-sheets which form the core component of amyloid plaques. Adapted from references [70, 71]

Fig. 5

Spatiotemporal pattern of Aβ deposition during the AD disease cascade in the human brain according to the Thal phases and to the “A” score. Thal phase 1 delineates cortical regions exhibiting the initial buildup of Aβ during the early pre-clinical stage. Subsequent accumulation extends to allocortical regions and the midbrain in Thal phases 2 and 3, while Aβ deposition in the cerebellum and brainstem occurs during late-phase clinical stages (Thal phases 4 and 5). Stage A0 represents individuals with asymptomatic amyloidosis; stage A1 combines Thal phases 1 and 2; stage A2 is equivalent to Thal phase 3; and stage A3 combines Thal phases 4 and 5. Blue areas represent the regions affected by Aβ deposition for each stage of neuropathology. Adapted from references [44, 45, 116]

Fig. 6

Illustration of different types of Aβ plaques found in AD patients. Adapted from reference [121]