%0 Journal Article
%A Soria Tobar, Lucía
%A Ouro-Corredera, Daniel
%A Román Valero, Laura
%A Hernández, Félix
%A Millán, José Luis
%A Álvarez Castelao, Beatriz
%A Sebastián Serrano, Álvaro
%A Aivar, Paloma
%A Díaz Hernández, Miguel
%T Neuronal alkaline phosphatase promotes the spread of Tau-induced pathology, and its blockade prevents neurodegeneration and memory loss
%D 2026
%@ 1933-7213
%U https://hdl.handle.net/20.500.14352/134516
%X Tauopathies, such as Alzheimer's disease (AD), are neurodegenerative disorders marked by abnormal intraneuronal aggregates of phosphorylated Tau protein. Unfortunately, no effective treatment is currently available. Since extracellular Tau (eTau) is essential for the spread of cerebral tauopathy, immunotherapy approaches using specific antibodies against Tau have been investigated. However, these strategies have shown limited applicability and benefit. Because previous in vitro studies reported that dephosphorylation of eTau by tissue-nonspecific alkaline phosphatase (TNAP) enhances its neurotoxicity, here we evaluate how neuronal TNAP contributes to Tau-induced neurotoxicity in vivo. To address this, we generated new transgenic mouse lines using Cre-lox technology to i) specifically delete TNAP in excitatory neurons of P301S mice, a well-characterized tauopathy model, or ii) induce neuronal TNAP overexpression in WT mice. Moreover, we compare the in vivo spreading capacity of phospho-eTau and dephospho-eTau-induced neurotoxicity. Our findings show that neuronal TNAP deletion in P301S mice reduces i) neuronal and synaptic loss, ii) the number of neurons with neurofibrillary tangles (NFTs), iii) reactive astrogliosis and microgliosis, and iv) brain calcifications; collectively, these changes lead to v) improved memory function in these mice. Conversely, overexpression of neuronal TNAP in WT mice alone is sufficient to cause i) loss of thalamic neurons and synaptic contacts, ii) formation of intracellular NFTs, iii) reactive gliosis, iv) brain calcifications, and v) memory impairment. These results demonstrate that neuronal TNAP promotes Tau-induced neurotoxicity spreading by facilitating eTau dephosphorylation, which confirms this ectoenzyme as a promising therapeutic target for tauopathies
%~