Isotope‐labeled amyloid‐β does not transmit to the brain in a prion‐like manner after peripheral administration

Abstract

Findings of early cerebral amyloid-b deposition in mice after peripheral injection of amyloid-b-containing brain extracts, and in humans following cadaveric human growth hormone treatment raised concerns that amyloid-b aggregates and possibly Alzheimer's disease may be transmissible between individuals. Yet, proof that Ab actually reaches the brain from the peripheral injection site is lacking. Here, we use a proteomic approach combining stable isotope labeling of mammals and targeted mass spectrometry. Specifically, we generate 13 C-isotope-labeled brain extracts from mice expressing human amyloid-b and track 13 C-lysine-labeled amyloid-b after intraperitoneal administration into young amyloid precursor protein-transgenic mice. We detect injected amyloid-b in the liver and lymphoid tissues for up to 100 days. In contrast, injected 13 C-lysine-labeled amyloid-b is not detectable in the brain whereas the mice incorporate 13 C-lysine from the donor brain extracts into endogenous amyloid-b. Using a highly sensitive and specific proteomic approach, we demonstrate that amyloid-b does not reach the brain from the periphery. Our study argues against potential transmissibility of Alzheimer's disease while opening new avenues to uncover mechanisms of pathophysiological protein deposition.

A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development

“…Formalin-fixed hemispheres were embedded in paraffin and cut into 4-μm-thick coronal sections using a rotation microtome (HM355S, Leica Biosystems GmbH, Nußloch, Germany) as described previously [ 75 , 76 , 77 , 204 , 205 , 206 , 207 , 208 , 209 , 210 ]. Sections (bregma +0.8 mm and −1.8 mm) were stained for microglia (IBA1, 1:1000, FUJIFILM Wako Chemicals Europe GmbH, 019–19741), astrocytes (GFAP, 1:500, Agilent, Santa Clara, CA, USA, Z033401-2) using a BOND-III ® automated immunostaining system (Leica Biosystems GmbH, Nußloch, Germany) with a hematoxylin counterstain (provided with the staining kit, Bond Polymer Refine Detection, DS9800).…”

The Role of Circulating Aβ Seeds in the Progression of Cerebral Amyloidosis

“…They concluded that intraperitoneally administrated Aβ does not reach the brain from the periphery nor does it play any significant role in exacerbating brain amyloidosis. 19 Conversely, studies in guinea pigs and nonhuman primate models of cerebral amyloidosis have found that peripherally administered labeled-Aβ reaches the brain, contributes to parenchymal amyloidosis, and co-localizes with Aβ plaques 20,21 (Figure 1A). The discrepancies noted by the study from Brackhan et al may be explained by the source of the inoculum and/or the utilization of specific Tg mouse models that might generate distinct Aβ species that therefore result in differences in the rate of amyloid pathology progression.…”

“…18 In a more recent publication, Brackhan et al generated 13C-lysine-labeled human Aβ from Tg mouse brain extracts that were intraperitoneally injected into young Tg mice. 19 They detected the inoculated Aβ in the liver and lymphoid tissues but not in the brain of treated animals. They concluded that intraperitoneally administrated Aβ does not reach the brain from the periphery nor does it play any significant role in exacerbating brain amyloidosis.…”

Impact of common ALDH2 inactivating mutation and alcohol consumption on Alzheimer’s disease

“…And C57BL/6J mice genetically modified to synthesize human Aβ only in the liver have been reported to have increased plasma and brain Aβ ( Lam et al, 2021 ). On the other hand, intraperitoneal administration of 13 C-isotope-labeled brain extracts from mice expressing human Aβ to APP Tg mice resulted in long-term detection of injected Aβ in liver and lymphoid tissue but not in brain ( Brackhan et al, 2022 ). It remains unclear what effect peripheral Aβ has on Aβ deposition in the brain.…”