Alzheimer’s disease (AD) is characterized by cognitive impairment and the presence of neurofibrillary tangles and senile plaques in the brain. Neurofibrillary tangles are composed of hyperphosphorylated tau, while senile plaques are formed by amyloid-β (Aβ) peptide. The amyloid hypothesis proposes that Aβ accumulation is primarily responsible for the neurotoxicity in AD. Multiple Aβ-mediated toxicity mechanisms have been proposed including mitochondrial dysfunction. However, it is unclear if it precedes Aβ accumulation or if is a consequence of it. Aβ promotes mitochondrial failure. However, AβPP could be cleaved in the mitochondria producing Aβ peptide. Mitochondrial-produced Aβ could interact with newly formed ones or with Aβ that enter the mitochondria, which may induce its oligomerization and contribute to further mitochondrial alterations, resulting in a vicious cycle. Another explanation for AD is the tau hypothesis, in which modified tau trigger toxic effects in neurons. Tau induces mitochondrial dysfunction by indirect and apparently by direct mechanisms. In neurons mitochondria are classified as non-synaptic or synaptic according to their localization, where synaptic mitochondrial function is fundamental supporting neurotransmission and hippocampal memory formation. Here, we focus on synaptic mitochondria as a primary target for Aβ toxicity and/or formation, generating toxicity at the synapse and contributing to synaptic and memory impairment in AD. We also hypothesize that phospho-tau accumulates in mitochondria and triggers dysfunction. Finally, we discuss that synaptic mitochondrial dysfunction occur in aging and correlates with age-related memory loss. Therefore, synaptic mitochondrial dysfunction could be a predisposing factor for AD or an early marker of its onset.

Background and Objective During cyclosporine‐induced gingival overgrowth, the homeostatic balance of gingival connective tissue is disrupted leading to fibrosis. Galectins are glycan‐binding proteins that can modulate a variety of cellular processes including fibrosis in several organs. Here, we study the role of galectin‐8 (Gal‐8) in the response of gingival connective tissue cells to cyclosporine. Methods We used human gingival fibroblasts and mouse NIH3T3 cells treated with recombinant Gal‐8 and/or cyclosporine for analyzing specific mRNA and protein levels through immunoblot, real‐time polymerase chain reaction, ELISA and immunofluorescence, pull‐down with Gal‐8‐Sepharose for Gal‐8‐to‐cell surface glycoprotein interactions, short hairpin RNA for Gal‐8 silencing and Student's t test and ANOVA for statistical analysis. Results Galectin‐8 stimulated type I collagen and fibronectin protein levels and potentiated CTGF protein levels in TGF‐β1‐stimulated human gingival fibroblasts. Gal‐8 interacted with α5β1‐integrin and type II TGF‐β receptor. Gal‐8 stimulated fibronectin protein and mRNA levels, and this response was dependent on FAK activity but not Smad2/3 signaling. Cyclosporine and tumor necrosis factor alpha (TNF‐α) increased Gal‐8 protein levels. Finally, silencing of galectin‐8 in NIH3T3 cells abolished cyclosporine‐induced fibronectin protein levels. Conclusion Taken together, these results reveal for the first time Gal‐8 as a fibrogenic stimulus exerted through β1‐integrin/FAK pathways in human gingival fibroblasts, which can be triggered by cyclosporine. Further studies should explore the involvement of Gal‐8 in human gingival tissues and its role in drug‐induced gingival overgrowth.