Impact of the presence of AβN3pE and AβpSer8 in Aβ aggregates on the induction of Aβ seeding and spreading in the brains of APP23 mice

Background Amyloid β‐plaques are a hallmark lesion of Alzheimer’s disease (AD) and consist of aggregates of the amyloid β‐peptide (Aβ). Aβ peptides can undergo posttranslational modifications, including N‐terminal truncation with subsequent pyroglutamate formation at glutamate 3, and phosphorylation at serine 8, leading to the formation of AβN3pE and AβpSer8, respectively. These posttranslationally modified forms are present in the brain in addition to non‐modified Aβ. During disease development the composition of the Aβ aggregates changes from aggregates without detectable modified Aβ, in non‐demented individuals, into aggregates containing AβN3pE and AβSer8 in symptomatic AD cases. Brain‐derived Aβ aggregates are capable of inducing deposition and spreading of Aβ pathology when injected into the brain of APP‐transgenic mice. Therefore, the question arises whether the composition of Aβ aggregates has impact on its seeding capabilities as well as on the composition of the seeded Aβ plaques. Method APP23 mice were injected into the left hippocampus at two months of age. They received injections from three different brain homogenates. The first one lacked detectable Aβ (control), in a second homogenate only Aβ without detectable modifications was found (p‐preAD), and in the third homogenate both Aβ and AβN3pE were detected. Mice were sacrificed at six months and their brains were immunohistochemically analyzed for the presence and composition of the induced plaque pathology. Result APP23 mice injected with the AD or p‐preAD brain homogenates developed similar Aβ plaque loads and the plaques exhibited AβN3pE and AβpSer8 immunoreactivity. Mice receiving control brain homogenates developed very few plaques in the injected hemisphere, which were detectable with antibodies against Aβ and AβN3pE, but not with anti‐AβpSer8. Conclusion The presence of Aβ seeds accelerates the accumulation of detectable amounts of AβN3pE and AβpSer8 and, thereby, promote the formation of fully mature Aβ aggregates similar to that seen in symptomatic AD patients. The acceleration of Aβ aggregate maturation, however, does not depend on the presence of posttranslationally modified Aβ forms in the seeds. Support: FWO.