ABSTRACT
Background:
Cognitive decline in
Alzheimer's disease (AD) is associated with
prion-like tau propagation between
neurons along synaptically connected networks, in part via
extracellular vesicles (EV). EV biogenesis is triggered by
ceramide enrichment at the
plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of
sphingomyelin. We
report, for the first
time, that tau expression triggers an elevation in
brain ceramides and nSMase2 activity.
Methods:
To determine the
therapeutic benefit of inhibiting this elevation, we evaluated the
efficacy of PDDC, the first potent, selective, orally bioavailable, and
brain-penetrable nSMase2 inhibitor, in the PS19 tau transgenic AD murine model. Changes in
brain ceramide and
sphingomyelin levels, Tau content, histopathology, and nSMase2 target engagement were monitored, as well as changes in the number of
brain-derived EVs in
plasma and their Tau content. Additionally, we evaluated the
ability of PDDC to impede tau propagation in a murine model where an
adeno-associated virus(AAV) encoding for P301L/S320F double mutant
human tau was stereotaxically-injected unilaterally into the
hippocampus and the contralateral transfer to the
dentate gyrus was monitored.
Results:
Similar to
human AD, PS19
mice exhibited increased
brain ceramides and nSMase2 activity; both were completely normalized by PDDC
treatment. PS19
mice exhibited elevated tau immunostaining, thinning of hippocampal neuronal
cell layers, increased mossy fiber
synaptophysin immunostaining, and glial activation, all pathologic features of
human AD. PDDC
treatment significantly attenuated these aberrant changes.
Mouse plasma isolated from PDDC-treated PS19
mice exhibited reduced levels of
neuron- and
microglia-derived EVs, the former
carrying lower phosphorylated Tau(pTau) levels, compared to untreated
mice. In the AAV tau propagation model, PDDC normalized the tau-induced increase in
brain ceramides and significantly decreased tau spreading to the contralateral side.
Conclusions:
PDDC is a first-in-class
therapeutic candidate that normalizes elevated
brain ceramides and nSMase2 activity leading to the slowing of tau spread in AD
mice.