Intracerebroventricular Streptozotocin Exacerbates Alzheimer-Like Changes of 3xTg-AD Mice

Alzheimer's disease (AD) involves several possible molecular mechanisms, including impaired brain insulin sig- naling and glucose metabolism. To investigate the role of metabolic insults in AD, we injected streptozotocin (STZ), a diabetogenic compound if used in the periphery, into the lateral ventricle of the 6-month-old 3xTg-AD mice and stud- ied the cognitive function as well as AD-like brain abnormal- ities, such as tau phosphorylation and Aβ accumulation, 3- 6 weeks later. We found that STZ exacerbated impairment of short-term and spatial reference memory in 3xTg-AD mice. We alsoobservedanincreaseintauhyperphosphorylationand neuroinflammation, a disturbance of brain insulin signaling, andadecreaseinsynapticplasticityandamyloid βpeptidesin the brain after STZ treatment. The expression of 20 AD- related genes, including those involved in the processing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulin signaling, synaptic function, protein kinases, and apo- ptosis, was altered, suggesting that STZ disturbs multiple metabolic and cell signaling pathways in the brain. These findings provide experimental evidence of the role of meta- bolic insult in AD.