Abstract
Little is known about the effects of parenchymal or vascular amyloid β peptide (Aβ) deposition in the brain. We hypothesized that Aβ strain-specific information defines whether Aβ deposits on the brain parenchyma or blood vessels. We investigated 12 autopsied patients with different severities of Aβ plaques and cerebral amyloid angiopathy (CAA), and performed a seeding study using an Alzheimer’s disease (AD) mouse model in which brain homogenates derived from the autopsied patients were injected intracerebrally. Based on the predominant pathological features, we classified the autopsied patients into four groups: AD, CAA, AD + CAA, and less Aβ. One year after the injection, the pathological and biochemical features of Aβ in the autopsied human brains were not preserved in the human brain extract-injected mice. The CAA counts in the mice injected with all four types of human brain extracts were significantly higher than those in mice injected with PBS. Interestingly, parenchymal and vascular Aβ depositions were observed in the mice that were injected with the human brain homogenate from the less Aβ group. The Aβ and CAA seeding activities, which had significant positive correlations with the Aβ oligomer ratio in the human brain extracts, were significantly higher in the human brain homogenate from the less Aβ group than in the other three groups. These results indicate that exogenous Aβ seeds from different Aβ pathologies induced Aβ deposition in the blood vessels rather than the brain parenchyma without being influenced by Aβ strain-specific information, which might be why CAA is a predominant feature of Aβ pathology in iatrogenic transmission cases. Furthermore, our results suggest that iatrogenic transmission of Aβ pathology might occur due to contamination of brain tissues from patients with little Aβ pathology, and the development of inactivation methods for Aβ seeding activity to prevent iatrogenic transmission is urgently required.
Highlights
Alzheimer’s disease (AD) is the most frequent cause of dementia, and senile plaques with extracellular deposition of amyloid β peptides (Aβ) and intracellular neurofibrillary tangles (NFTs) with abnormally phosphorylated tau protein are pathological hallmarks of AD [28]
In the present study, the morphological features of Aβ pathology, such as cored plaques, diffuse plaques, and Cerebral amyloid angiopathy (CAA), were clearly different among the AD, CAA, AD + CAA and less Aβ groups in the autopsied patients, those in the R1.40 mice injected with the human brain extracts were very similar among the four groups
The Aβ proteinase K (PK) resistance of the human brain extracts was different among the different patient groups, which might be due to differences in the Aβ strain, while the PK resistance in the mouse brain extracts was not different among the groups
Summary
Alzheimer’s disease (AD) is the most frequent cause of dementia, and senile plaques with extracellular deposition of amyloid β peptides (Aβ) and intracellular neurofibrillary tangles (NFTs) with abnormally phosphorylated tau protein are pathological hallmarks of AD [28]. Seven amyloid proteins that involve the vessels of patients with CAA have been reported, with Aβ being the most common amyloid protein in patients with CAA [63, 65]. Aβ40 does not aggregate as as Aβ42, whereas Aβ42 promptly deposits in the brain parenchyma as senile plaques. Most patients with CAA have accompanying parenchymal Aβ deposition, there have been reports of pure CAA patients with fewer of Aβ depositions or NFTs in the brain parenchyma, as well as AD patients presenting without CAA [33, 57, 59]. The precise reason why Aβ deposits in the brain parenchyma or blood vessels has not been elucidated
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