Intravenous treatment with a molecular chaperone designed against β-amyloid toxicity improves Alzheimer’s disease pathology in mouse models

Molecular Mechanisms of Amyloid-β Self-Assembly Seeded by In Vivo-Derived Fibrils and Inhibitory Effects of the BRICHOS Chaperone

“…Further, the inhibitory effect of BRICHOS, as an example of a molecular chaperone targeting amyloid generation, is transferable from in vitro to in vivo-derived fibril-seeded Aβ42 aggregation kinetics, pointing toward a similar mechanism of action of preventing Aβ42 self-assembly being present in vivo. This provides a molecular understanding of how protein-based treatments can attenuate neuroinflammation and improve cognitive behavior in AD mouse models, , directing ways on how molecular chaperones can be utilized to combat toxic amyloid formation in neurodegenerative diseases.…”

“…22,23 Importantly, a recent study wherein App NL-F and App NL-G-F mice were intravenously treated with recombinant human (rh) Bri2 BRICHOS showed reduced neuroinflammation and improved working memory and object recognition. 24,42 Whether the molecular mechanism of Aβ aggregation accelerated by in vivo-derived Aβ42 fibrils is the same as that for in vitro fibrils is still an open question. In addition, further research is demanded on whether the inhibitory mechanism of BRICHOS on Aβ42 self-assembly determined in vitro can be linked to the observed effects in the treatment studies of AD mice.…”

“…12 Immuno-stained images of brain sections confirmed abundant Aβ42 plaques in both App NL-F and App NL-G-F brain tissues (Figure 1B). The mouse brains were dissected, 24 homogenized in Tris-calcium buffer, pH 8.0, and centrifuged, where the procedure was repeated three times in total (see Materials and Methods). After digestion with collagenase and DNAase I, the pellet was washed twice with a sodium dodecyl sulfate (SDS) buffer and washing buffer.…”

Abilities of the BRICHOS domain to prevent neurotoxicity and fibril formation are dependent on a highly conserved Asp residue

“…[22][23][24][25] For instance, recombinant human (rh) BRI-CHOS domains recognise and bind to amyloid fibrils of amyloid b-peptide (Ab, linked to AD) and islet amyloid polypeptide (IAPP, linked to T2D), and reduce their cellular toxicity, [25][26][27] bind the smallest emerging toxic Ab oligomers, 24 bind to amyloid fibrils of Huntingtin (linked to Huntington's disease) and a-synuclein (linked to Parkinson disease), 28 and can be used to efficiently reduce Ab neurotoxicity in mouse hippocampal slice preparations and in vivo in animal models of AD. 27,[29][30][31][32][33] This broad anti-amyloid spectrum makes BRICHOS a potential candidate for amyloid disease prevention and even treatment.…”

OAF: a new member of the BRICHOS family

“…This anti-amyloidogenic function of BRICHOS domains has been explored as a potential therapeutic agent, seeking to prevent aggregation of the Aβ42 polypeptide in Alzheimer disease ( Hermansson et al , 2014 ; Manchanda et al , 2022 ; Nerelius et al , 2009 ; Poska et al , 2016 , 2020 ), the islet amyloid polypeptide (IAPP) in type 2 diabetes ( Oskarsson et al , 2018 ) or mutated NOTCH3 protein in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) ( Oliveira et al , 2022 ).…”