Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies

Abstract

The amyloid-β protein (Aβ) protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). It is believed that Aβ deposited in the brain originates from the brain tissue itself. However, Aβ is generated in both brain and peripheral tissues. Whether circulating Aβ contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aβ originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis. AD-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery.

Intravenously Injected Amyloid-β Peptide With Isomerized Asp7 and Phosphorylated Ser8 Residues Inhibits Cerebral β-Amyloidosis in AβPP/PS1 Transgenic Mice Model of Alzheimer’s Disease

“…Its amyloidogenicity was later attributed to the metal-binding domain isoD7-Aβ16 (Kulikova et al, 2016). The ability of peripherally derived Aβ species to directly contribute to AD pathogenesis has been recently confirmed in an independent study (Bu et al, 2017). …”

Senile plaques in Alzheimer’s disease arise from Aβ and Cathepsin D-enriched amyloidogenic mixtures out of intravascular hemolysis and Charcot-Bouchard aneurysm-related vascular degeneration

“…Senile plaque Aβ has been hypothesized to be derived from neural or vascular/blood source 8,12,15,25 . Platelets and red blood cells are proposed to be two main cellular sources of Aβ in the blood [26][27][28][29] .…”

“…However, the mechanism governing Aβ generation in senile plaques and the linkage between CAA and senile plaques is still not clear. Most researchers believed that senile plaques are derived from neuronal cells as proposed in amyloid cascade hypothesis 7,8 , on the other hand, there is also strong evidence showing that senile plaques are linked with cerebral microhemorrhage [9][10][11][12][13][14][15][16] . We used immunohistchemistry, fluorescence imaging and TUNEL assay to examine the neural, vascular or blood Aβ contribution to senile plaque development.…”

Vascular and non‐vascular contributors to memory reduction during traumatic brain injury

“…It is known that Aβ is generated in both brain and peripheral tissues and it is circulated in blood (Evin, Zhu, Holsinger, Masters, & Li, ), where its level is correlated with increased risk of AD development (Graff‐ Radford et al., ; van Oijen, Hofman, Soares, Koudstaal, & Breteler, ; Schupf et al., ). Studies showed that blood‐derived Aβ can enter the brain and induce neuronal dysfunction (Bu et al., ; Zlokovic, ). Transport of Aβ through BBB has major role in accumulation of Aβ in CNS (Deane et al., ).…”