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Wnt signaling loss accelerates the appearance of neuropathological hallmarks of Alzheimer's disease in J20‐ APP transgenic and wild‐type mice
Author(s) -
TapiaRojas Cheril,
Inestrosa Nibaldo C.
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14278
Subject(s) - wnt signaling pathway , genetically modified mouse , hippocampus , phosphorylation , transgene , biology , medicine , endocrinology , neuroprotection , alzheimer's disease , signal transduction , microbiology and biotechnology , senile plaques , hippocampal formation , neuroscience , disease , biochemistry , gene
Alzheimer's disease ( AD ) is a neurodegenerative pathology characterized by aggregates of amyloid‐β (Aβ) and phosphorylated tau protein, synaptic dysfunction, and spatial memory impairment. The Wnt signaling pathway has several key functions in the adult brain and has been associated with AD , mainly as a neuroprotective factor against Aβ toxicity and tau phosphorylation. However, dysfunction of Wnt/β‐catenin signaling might also play a role in the onset and development of the disease. J20 APP swInd transgenic (Tg) mouse model of AD was treated i.p. with various Wnt signaling inhibitors for 10 weeks during pre‐symptomatic stages. Then, cognitive, biochemical and histochemical analyses were performed. Wnt signaling inhibitors induced severe changes in the hippocampus, including alterations in Wnt pathway components and loss of Wnt signaling function, severe cognitive deficits, increased tau phosphorylation and Aβ 1–42 peptide levels, decreased Aβ42/Aβ40 ratio and Aβ 1–42 concentration in the cerebral spinal fluid, and high levels of soluble Aβ species and synaptotoxic oligomers in the hippocampus, together with changes in the amount and size of senile plaques. More important, we also observed severe alterations in treated wild‐type ( WT ) mice, including behavioral impairment, tau phosphorylation, increased Aβ 1–42 in the hippocampus, decreased Aβ 1–42 in the cerebral spinal fluid, and hippocampal dysfunction. Wnt inhibition accelerated the development of the pathology in a Tg AD mouse model and contributed to the development of Alzheimer's‐like changes in WT mice. These results indicate that Wnt signaling plays important roles in the structure and function of the adult hippocampus and suggest that inhibition of the Wnt signaling pathway is an important factor in the pathogenesis of AD .Read the Editorial Highlight for this article on page 356.