Sex‐Specific Neurotoxicity of Dietary Advanced Glycation End Products in APP/PS1 Mice and Protective Roles of Trehalose by Inhibiting Tau Phosphorylation via GSK‐3β‐TFEB

Abstract

ScopeIt remains unclear whether dietary advanced glycation end products (dAGEs)‐induced cognitive impairment is sex‐dependent. Trehalose may antagonize dAGEs‐induced neurotoxicity via glycogen synthase kinase‐3 beta (GSK3β)‐transcription factor EB (TFEB) signaling.Methods and ResultsThe sex‐specific neurotoxicity of dAGEs and the protective role of trehalose are investigated both in vivo and in vitro. Both sexes of APP/PS1 mice are divided into three groups: that is, control, dAGEs, and dAGEs supplemented with trehalose. SHSY‐5Y cells incubated with AGE‐BSA and trehalose are also utilized. Dietary AGEs impair cognitive function only in female mice, which is restored by trehalose. Trehalose upregulates phosphorylated‐GSK3β serine9 (p‐GSK3β ser9), TFEB and transient receptor potential mucolipin 1, ADAM10, oligosaccharyl transferase‐48, estrogen receptor α and induces TFEB nuclear translocation in hippocampus, elevates IDE and ERβ in cortex, while reduces p‐tau ser396&404, CDK5, cathepsin B, and glial fibrillary acidic protein in hippocampus. Trehalose elevates p‐GSK3β ser9, induces TFEB nuclear translocation, consequently reverses AGE‐BSA‐induced tau phosphorylation in vitro.ConclusionsFemale mice are more susceptible to the deleterious effects of dAGEs on cognitive function, which may be owing to its regulation on ERβ. Trehalose can strongly reverse dAGEs‐induced tau phosphorylation by potentiating TFEB nuclear translocation via inhibiting GSK‐3β.

Posttreatment with PaPE-1 Protects from Aβ-Induced Neurodegeneration Through Inhibiting the Expression of Alzheimer’s Disease-Related Genes and Apoptosis Process That Involves Enhanced DNA Methylation of Specific Genes

“…Since GSK3β activity is determined by its phosphorylation on specific sites, and only the active GSK3β is a measure of apoptosis, we do not interpret PaPE-1-evoked increase in the control level of GSK3β as a proapoptotic effect. GSK3β inhibition was observed in response to trehalose, which upregulated ERα and ERβ and protected APP/PS1 mice against dietary advanced glycation end product (dAGE)-induced neurotoxicity and cognitive impairment [ 53 ]. Our results are also in line with the ERα-mediated anti-apoptotic effects of adenosine against Aβ 25-35 -induced brain damage [ 54 ] and of formononetin in AD patients [ 55 ], as well as the ER/PI3K/Akt-mediated effect of naringenin against Aβ 25-35 -caused damage in neuronally differentiated PC12 cells [ 56 ].…”

Age-dependent effects of a high-fat diet combined with dietary advanced glycation end products on cognitive function and protection with voluntary exercise

“…4 Additionally, dietary advanced glycation end products (AGEs), which typically increase when high-temperature cooking methods are involved, such as deep-frying, broiling, and roasting, and are prone to accumulate in foods high in protein and/or fat contents, 5 is another increasingly recognized dietary risk factor associated with cognitive decline (AD). 6 Previous animal studies have also supported the idea that an AGEs diet might induce cognitive impairment via multiple mechanisms, 7–10 such as affecting mitochondrial function 11 or hallmarks involved in AD. 8 It remains unclear whether the combination of HFD with AGEs diet might induce worse cognitive dysfunction than independent intervention.…”

GSK3: A potential target and pending issues for treatment of Alzheimer's disease

“…Treatment with trehalose mitigated the negative effect of AGEs through down‐regulation of GSK3β and triggered nuclear translocation of transcription factor EB (TFEB). 291 Similarly, Calycosin exhibits a neuroprotective effect against AGEs‐induced neurotoxicity by inhibiting GSK3β. In a rat model of diabetes complicated with AD, Calycosin improves learning and memory, and reduces AD‐related pathologies such as neurofibrillary tangles and amyloid deposits, as well as mitochondrial dysfunction.…”

“…AGEs increased GSK3β activity and tau phosphorylation in female APP/PS1 mice. Treatment with trehalose mitigated the negative effect of AGEs through down‐regulation of GSK3β and triggered nuclear translocation of transcription factor EB (TFEB) 291 . Similarly, Calycosin exhibits a neuroprotective effect against AGEs‐induced neurotoxicity by inhibiting GSK3β.…”