Treatments with Lithium and Rosiglitazone reduce the amount of total Aβ in brains of APPswe+PSEN1ΔE9 mice. (A) Hippocampal and cortical slices from transgenic mice APPswe+PSEN1ΔE9 (Tg) stained against Aβ. Photos are of Tg control and Tg treated animals with Lithium or Rosiglitazone. Figures B and C show the average Aβ plaque area (μm²) in the hippocampus and cortex after the treatments of lithium (B) and rosiglitazone (C) respectively, with bars representing the average plaque area for each specific treatment ± S.E (n = 5). Asterisks indicate significant differences, p < 0.05.

Activation of α7nAChR with nicotine protects hippocampal neurons from Aβ fibers. (A) Hippocampal neurons (10 DIV) were expose to Aβ_1–40 fibers 5 mM for 6 h in the absence or presence of nicotine 10 μM. The immunostainings of the protein neurofilament (NF) shows the loss of dendrites, and the presynaptic protein SV-2, show a significant reduction upon exposure to Aβ. Nicotine is able to overturn the damage cause by Aβ. This reversion is specific to the nicotinic receptor since this protective effect was blocked by α-bungarotoxin (100 nM). (B) These effects are observed by western-blot of the total levels of total β-catenin, in which the reduction of β-catenin is prevented by nicotine and blocked with α-BTX.

The Wnt signaling pathway and its inhibition by Aβ aggregates. First when the Wnt ligand is available, the Fz receptor together with LRP5/6 translates its signal through Dvl, which in turn inactivates GSK-3β in the cytoplasmic destruction complex. This allows β-catenin to accumulate in the cytoplasm, and subsequently to move to the nucleus, where it binds to TCF/LEF transcription factors activating Wnt target gene transcription (Left Panel). On the other hand, when the Aβ aggregates become available, the signaling through the Wnt pathway might be affected: GSK-3β activates, β-catenin destroyed, and the Wnt mediated gene transcription is stopped (Right Panel). Several potential mechanisms of how Aβ aggregates affect Wnt signaling might be possible: (a) Aβ may bind to the Wnt ligand (scavenger effect), (b) Aβ may directly interact with the Fz receptor, (c) Dkk-1 may become available and block the transduction at the receptor level, or (d) Aβ may affect calcium flux by direct activation of the α7-nicotinic ACh and/or NMDA receptors. As a consequence, GSK-3β is activated and β-catenin function attenuated.