Amyloid pathology refers to the accumulation and deposition of misfolded proteins in tissues and organs. In Alzheimer's disease, amyloid-beta (Aβ) peptides aggregate to form plaques, which are considered a central pathological feature of the disease [1]. [@charidimou2015]
Amyloid-beta is a peptide derived from the amyloid precursor protein (APP) through sequential proteolytic cleavage by beta-secretase (BACE) and gamma-secretase [2]. The amyloidogenic processing pathway generates Aβ peptides of varying lengths, with Aβ40 being the most abundant species and Aβ42 being more aggregation-prone due to two additional hydrophobic residues at the C-terminus [3]. [@weller2000]
The aggregation of Aβ follows a nucleation-dependent polymerization mechanism: [@jellinger2005]
- Monomeric Aβ → Oligomers → Protofibrils → Fibrils → Plaques [4]
- Soluble oligomers are considered more toxic than plaques [5]
- Different Aβ species: Aβ40, Aβ42, Aβ43 [3]
- The critical concentration for nucleation is lower for Aβ42 compared to Aβ40 [6]
- Dense-core plaques
- Contain Aβ fibrils in cross-β sheet conformation [7]
- Surrounded by dystrophic neurites
- Associated with neuritic plaques in AD diagnosis [8]
- Non-fibrillar Aβ deposits
- Less well-defined borders
- May be earlier stage of plaque formation [9]
- Can be found in cognitively normal individuals [10]
- Deposited in cerebral blood vessels
- Associated with hemorrhage risk [11]
- Perivascular clearance impaired [12]
- CAA affects ~80% of AD cases to some degree [13]
- Soluble Aβ oligomers disrupt synaptic function [14]
- Loss of dendritic spines [15]
- Impaired neurotransmitter release [16]
- Synaptic loss correlates strongly with cognitive decline [17]
- Aβ forms membrane pores allowing calcium influx [18]
- Mitochondrial dysfunction from calcium overload [19]
- Cellular energy deficits and ATP depletion [20]
- Microglial activation via pattern recognition receptors [21]
- Cytokine release (IL-1β, TNF-α, IL-6) [22]
- Chronic inflammatory response contributes to neurodegeneration [23]
- Trem2 variants affect microglial response to amyloid [24]
- Amyloid triggers tau pathology [25]
- Spread along neural networks [26]
- Correlation with cognitive decline [27]
- Amyloid-tau interaction is synergistic [28]
Amyloid fibrils adopt a characteristic cross-β sheet quaternary structure where β-strands run perpendicular to the fibril axis [7]. This structure is stabilized by hydrogen bonds between backbone amide and carbonyl groups, as well as side-chain interactions. Different Aβ strains can adopt distinct conformations, potentially explaining phenotypic heterogeneity in AD [29]. [@shankar2008]
Aβ fibrils exhibit structural polymorphism, with distinct morphologies observed in different individuals and brain regions [30]. This polymorphism may influence disease progression and therapeutic response [31]. [@spires2005]
¶ Nucleation and Elongation
The aggregation process follows sigmoidal kinetics with three phases: [@kamenetz2003]
- Nucleation (lag phase): Formation of critical nucleus [32]
- Elongation (growth phase): Addition of monomers to fibril ends [33]
- Equilibrium (plateau phase): Dynamic balance [34]
- Concentration: Higher Aβ concentration accelerates aggregation [35]
- pH: Optimal aggregation at physiological pH [36]
- Metal ions: Cu²⁺ and Zn²⁺ promote aggregation [37]
- Post-translational modifications: Oxidation, phosphorylation affect kinetics [38]
- Aducanumab: Anti-Aβ antibody (withdrawn from market) [39]
- Lecanemab: Anti-protofibril antibody (approved for early AD) [40]
- Donanemab: Anti-plaque antibody (approved for early AD) [41]
- Donanemab demonstrated significant plaque reduction in TRAILBLAZER-ALZ 2 trial [42]
- BACE inhibitors: Failed due to adverse effects [43]
- Gamma-secretase modulators: In development [44]
- Small molecules to prevent aggregation [45]
- Peptide-based inhibitors [46]
- Chaperone proteins (Hsp70, Hsp90) [47]
This section highlights recent publications relevant to this mechanism. [@terry1991]
Additional evidence sources: [@arispe1993] [@wang1992] [@mattson1997] [@hickman2010] [@griffin1998] [@heppner2015] [@griciuc2013] [@musiek2015] [@braak2011] [@nelson2012] [@ittner2018] [@cohen2023] [@guo2023] [@riek2016] [@knowles2009] [@carulla2005] [@sengupta2023] [@lomakin1996] [@gursky2000] [@bush2002] [@crouch2009] [@sevigny2016] [@van2023] [@mintun2021] [@sims2023] [@bace2018] [@bales2021] [@lupi2008] [@soto1996] [@evans2006]