Seeding, maturation and propagation of amyloid beta-peptide aggregates in Alzheimer's disease

Alzheimer's disease is neuropathologically characterized by the deposition of the amyloid beta-peptide (A beta) as amyloid plaques. A beta plaque pathology starts in the neocortex before it propagates into further brain regions. Moreover, A beta aggregates undergo maturation indicated by the occurrence of post-translational modifications. Here, we show that propagation of A beta plaques is led by presumably non-modified A beta followed by A beta aggregate maturation. This sequence was seen neuropathologically in human brains and in amyloid precursor protein transgenic mice receiving intracerebral injections of human brain homogenates from cases varying in A beta phase, A beta load and A beta maturation stage. The speed of propagation after seeding in mice was best related to the A beta phase of the donor, the progression speed of maturation to the stage of A beta aggregate maturation. Thus, different forms of A beta can trigger propagation/maturation of A beta aggregates, which may explain the lack of success when therapeutically targeting only specific forms of A beta.