Jan Johansson

Amyloid is associated with Alzheimer´s disease (AD) in which Aβ42 and tau form fibrils, and with Parkinson´s disease (PD) where α-synuclein (α-syn) aggregates into fibrils. Targeting amyloid in the CNS is complicated by the blood-brain barrier (BBB) and the location of tau and α-syn fibrils inside neurons. We have shown that the molecular chaperone BRICHOS can be used to treat Aβ toxicity in AD models, and that it passes the BBB and into neurons. Recent data show how BRICHOS blocks a hotspot for toxic oligomer formation on Aβ42 fibrils, and that BRICHOS treatment of AD mice affects the expression of several risk genes for human AD. Moreover, BRICHOS can carry cargo proteins over the BBB and into neurons. We will study how BRICHOS (i) prevents Aβ neurotoxicity on molecular and cellular levels

(ii) works against tau and α-syn neurotoxicity in vitro and in AD and PD mouse models

(iii) can transport antibodies, neurotrophins and lysosomal enzymes over the BBB and into neurons. We will also (iv) identify receptors and transport pathways that mediate BRICHOS transcytosis over endothelial cells and uptake into the neuronal endolysosomal compartment. The project tackles large unmet medical needs and is centered around the recombinant BRICHOS domain, which has an apparently unique potential for development of new therapies against neurodegeneration and neurological diseases.