Soluble Brain Homogenates from Diverse Human and Mouse Sources Preferentially Seed Diffuse Aβ Plaque Pathology When Injected into Newborn Mouse Hosts

Background Seeding of pathology related to Alzheimer’s disease (AD) and Lewy body disease (LBD) by the injection of tissue homogenates, purified proteins, or recombinant proteins into model systems has revealed prion-like seeding of the protein aggregates that define these disorders. Most commonly these homogenates are injected into adult mice stereotaxically. Injection of brain lysates into newborn mice represents an alternative approach of delivering seeds that could be used to direct the evolution of amyloid-β (Aβ) pathology co-mixed with either tau or α-synuclein (αSyn) pathology in vulnerable mouse models. Methods Homogenates of human pre-frontal cortex were prepared and injected into the lateral ventricles of newborn (P0) mice expressing a mutant humanized amyloid precursor protein (APP), human P301L tau, human wild type αSyn, or combinations thereof. The injected brain homogenates were prepared from AD and AD/LBD cases displaying variable degrees of Aβ pathology and co-existing tau and αSyn deposits. Behavioral assessments of APP transgenic mice injected with AD brain lysates were conducted. Results We observed that the lysates from the brains of individuals with AD (Aβ+, tau+), AD/LBD (Aβ+, tau+, αSyn+), or Pathological Aging (Aβ+, tau-, αSyn-) efficiently seeded diffuse Aβ deposits, composed primarily of Aβ42 peptides, in our transgenic host animals. Moderate seeding of cerebral amyloid angiopathy (CAA) was also observed. No animal of any genotype developed discernable tau or αSyn pathology. Fear conditioning, cognitive, outcome was not significantly altered in APP transgenic animals injected with AD brain lysates compared to nontransgenic controls. Conclusions These findings demonstrate that diffuse Aβ pathology, which is a common feature of AD, AD/LBD, and PA brains, can be easily induced by injecting newborn APP mice with crude brain homogenates. Seeding of tau or αSyn comorbidities was disappointingly inefficient in the models we used, indicating additional methodological refinement will be needed to efficiently seed AD or AD/LBD mixed pathologies by injecting newborn mice.