HeparAlz

Alzheimer’s disease (AD), the most prevalent form of dementia, constitutes an increasing social and economic burden for which no effective therapies are available, calling for a better understanding of the physiopathological processes leading to the disease. AD brains contain characteristic misfolded aggregates of amyloid ß and of microtubule associated protein tau, which extent best correlates with cognitive symptoms. Tau misfolding spreads through neurons via a prion-like mechanism where tau seeds traffic from cell-to-cell and recruit endogenous tau into self-perpetuating aggregates. The exact mechanisms leading to tau spreading and subsequent tau aggregation are not fully deciphered. However, heparan sulfate (HS), the glycanic chains of HS proteoglycans (HSPG), act as cellular receptors for tau seeds uptake and are known to induce tau aggregation in vitro. In neurons, HS carry a 3-O-sulfation (n3S-HS) introduced by neuronal 3-O-sulfotransferases (HS3STs), in particular HS3ST2. Under physiological conditions n3S-HS are membrane-associated, whereas in AD they strongly accumulate in neurons affected by tauopathy, suggesting involvment in the tau aggregation process. The HeparAlz hypothesis are 1) that cell membrane-associated n3S-HS act as dual modulators of tauopathy by acting as receptors for tau proteopathic seeds and promoters of tau aggregation, and 2) that soluble HS-analogues can compete with endogenous cell membrane-associated n3S-HS to mitigate tau pathology. We will dissect the cellular mechanisms by which Hs3st2/n3S-HS modulate cellular uptake of AD-Tau seeds and subsequent tau aggregation. In vivo, we will assess the Hs3st2 depletion on tau spreading and aggregation and investigate how cell membrane n3S-HS competitors FP6 and enoxaparin affect tau spreading and aggregation. The HeparAlz project will provide invaluable insights into tau transcellular spreading and open to new perspectives for therapeutic development.