Alzheimer's disease is neuropathologically characterized by the deposition of the amyloid β-peptide (Aβ) as amyloid plaques. Aβ plaque pathology starts in the neocortex before it propagates into further brain regions. Moreover, Aβ aggregates undergo maturation indicated by the occurrence of post-translational modifications. Here, we show that propagation of Aβ plaques is led by presumably non-modified Aβ followed by Aβ 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 Aβ phase, Aβ load and Aβ maturation stage. The speed of propagation after seeding in mice was best related to the Aβ phase of the donor, the progression speed of maturation to the stage of Aβ aggregate maturation. Thus, different forms of Aβ can trigger propagation/maturation of Aβ aggregates, which may explain the lack of success when therapeutically targeting only specific forms of Aβ.
Keywords: Alzheimer’s disease; amyloid β protein; human brain; maturation and propagation; mouse model; seeding.
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