Knockout of p75 neurotrophin receptor attenuates the hyperphosphorylation of Tau in pR5 mouse model.

Abstract

p75 neurotrophin receptor (p75NTR) has been implicated in Alzheimer's disease (AD). However, whether p75NTR is involved in Tau hyperphosphorylation, one of the pathologies observed in AD, remains unclear. In our previous study, the extracellular domain of p75NTR blocked amyloid beta (Aβ) toxicity and attenuated Aβ-induced Tau hyperphosphorylation. Here we show that, in the absence of Aβ, p75NTR regulates Tau phosphorylation in the transgenic mice with the P301L human Tau mutation (pR5). The knockout of p75NTR in pR5 mice attenuated the phosphorylation of human Tau. In addition, the elevated activity of kinases responsible for Tau phosphorylation including glycogen synthase kinase 3 beta; cyclin-dependent-kinase 5; and Rho-associated protein kinase was also inhibited when p75NTR is knocked out in pR5 mice at 9 months of age. The increased caspase-3 activity observed in pR5 mice was also abolished in the absence of p75NTR. Our study also showed that p75NTR is required for Aβ- and pro-brain derived neurotrophin factor (proBDNF)-induced Tau phosphorylation, in vitro. Overall, our data indicate that p75NTR is required for Tau phosphorylation, a key event in the formation of neurofibrillary tangles, another hallmark of AD. Thus, targeting p75NTR could reduce or prevent the pathologic hyperphosphorylation of Tau.

• Authors: Noralyn B Mañucat-Tan, Lin-Lin Shen, Larisa Bobrovskaya, Mohammed Al-Hawwas, Fiona H Zhou, Yan-Jiang Wang, Xin-Fu Zhou
• Journal: Aging (Aging (Albany NY)) Vol. 11 Issue 17 Pg. 6762-6791 (09 03 2019) ISSN: 1945-4589 [Electronic] United States
• PMID: 31479419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptor, Nerve Growth Factor
• tau Proteins

Topics

• Alzheimer Disease (metabolism)
• Animals
• Disease Models, Animal
• Humans
• Mice
• Mice, Knockout
• Mice, Transgenic
• Mutation
• Phosphorylation
• Receptor, Nerve Growth Factor (metabolism)
• tau Proteins (genetics, metabolism)