Extracellular protein aggregate

Extracellular protein aggregates are non-native, often insoluble assemblies of proteins that have lost their functional conformation and polymerized into higher-order structures such as oligomers and amyloid fibrils (Chiti & Dobson, 2017, Annual Review of Biochemistry). These aggregates are a hallmark of various protein misfolding diseases or proteopathies, where they exert toxicity by disrupting cell membranes, inducing oxidative stress, and triggering inflammatory responses (Soto & Pritzkow, 2018, Nature Neuroscience). In the extracellular space, these aggregates can act as seeds that propagate pathology between cells, a process observed in neurodegenerative conditions like Alzheimer's disease and systemic amyloidoses (Soto & Pritzkow, 2018, Nature Neuroscience). Therapeutic strategies targeting these aggregates include monoclonal antibodies designed to facilitate their clearance by the immune system, small molecules that stabilize the protein's native state to prevent initial misfolding, and agents that directly disrupt the stability of established fibrils (Budd Haeberlein et al., 2022, J Prev Alzheimers Dis; Maurer et al., 2018, N Engl J Med). Clinical success with agents like lecanemab has validated the approach of reducing aggregate burden to slow cognitive decline in Alzheimer's disease (van Dyck et al., 2023, N Engl J Med).

Other names

Amyloid depositProtein aggregateMisfolded protein assemblyPathological protein aggregateExtracellular amyloidAmyloid fibrilToxic oligomer

Monoclonal antibodies bind to specific epitopes on misfolded or aggregated proteins to promote microglial-mediated clearance via phagocytosis (Budd Haeberlein et al., 2022, J Prev Alzheimers Dis). Small molecules may stabilize the native protein tetramer or monomer to prevent the initial misfolding event (Maurer et al., 2018, N Engl J Med), or directly disrupt the non-covalent interactions holding the aggregate together to promote dissolution.