Tau deletion reduces plaque‐associated BACE 1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease

Abstract In Alzheimer's disease, BACE 1 protease initiates the amyloidogenic processing of amyloid precursor protein ( APP ) that eventually results in synthesis of β‐amyloid (Aβ) peptide. Aβ deposition in turn causes accumulation of BACE 1 in plaque‐associated dystrophic neurites, thereby potentiating progressive Aβ deposition once initiated. Since systemic pharmacological BACE inhibition causes adverse effects in humans, it is important to identify strategies that specifically normalize overt BACE 1 activity around plaques. The microtubule‐associated protein tau regulates axonal transport of proteins, and tau deletion rescues Aβ‐induced transport deficits in vitro . In the current study, long‐term in vivo two‐photon microscopy and immunohistochemistry were performed in tau‐deficient APPPS 1 mice. Tau deletion reduced plaque‐associated axonal pathology and BACE 1 accumulation without affecting physiological BACE 1 expression distant from plaques. Thereby, tau deletion effectively decelerated formation of new plaques and reduced plaque compactness. The data revealed that tau reinforces Aβ deposition, presumably by contributing to accumulation of BACE 1 in plaque‐associated dystrophies. Targeting tau‐dependent mechanisms could become a suitable strategy to specifically reduce overt BACE 1 activity around plaques, thereby avoiding adverse effects of systemic BACE inhibition.