Impaired Glucose Tolerance and Reduced Plasma Insulin Precede Decreased AKT Phosphorylation and GLUT3 Translocation in the Hippocampus of Old 3xTg-AD Mice.
Level 5 - mechanism / opinion, no new human data
Animal research in a transgenic mouse model
PubMed 30775979 · doi:10.3233/JAD-180707
What was done
The authors investigated the timeline of peripheral glucose intolerance relative to central neuropathology and hippocampal insulin signaling in the triple transgenic mouse model of Alzheimer's disease (3xTg-AD). Mice were assessed at pre-pathology (1–3 months and 6–8 months) and post-pathology (16–18 or 18–20 months) stages using glucose tolerance tests, insulin tolerance tests, and plasma insulin ELISAs. Hippocampal tissue was evaluated via Western blot to measure activation of the PI3K/AKT and MAPK/ERK pathways, along with downstream targets including GSK3 and GLUT3 translocation.
What was found
3xTg-AD mice displayed impaired glucose tolerance and decreased plasma insulin levels beginning at 1 month of age and persisting across all tested time points, preceding amyloid-β plaques (~14 months), hyperphosphorylated tau aggregates (~18 months), and cognitive decline (≥18 months). Alterations in hippocampal PI3K/AKT signaling and reduced GLUT3 membrane translocation were detected only in 18–20-month-old mice; MAPK/ERK signaling was not altered. The abstract reports no numerical values, effect sizes, or variance measures.
Why it matters
This study demonstrates that systemic metabolic dysfunction occurs long before classic neuropathology and central insulin signaling failure in a standard Alzheimer's model, supporting energy metabolism disruptions as early events in disease pathogenesis.
Limits
Findings from a transgenic mouse model cannot be directly assumed to reflect human sporadic Alzheimer's disease. The abstract does not report sample sizes, specific numerical measurements, or statistical significance values. The temporal association does not establish a definitive causal mechanism between early peripheral insulin deficits and late central GLUT3 reductions.
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- supports Internalization or impairment of neuronal GLUT3 glucose transporters is linked to Alzheimer's disease pathology.