Cognitive Dysfunction and Anxiety Resulting from Synaptic Downscaling, Hippocampal Atrophy, and Ventricular...

Insulin-resistant brain state is proposed to be the early sign of Alzheimer's disease (AD), which can be studied in the intracerebroventricular streptozotocin (ICV-STZ) rodent model. ICV-STZ is reported to induce sporadic AD with the majority of the disease hallmarks as phenotype. On the other hand, available experimental evidence has used varying doses of STZ (< 1 to 3 mg/kg) and studied its effect for different study durations, ranging from 14 to 270 days. Though these studies suggest 3 mg/kg of ICV-STZ to be the optimum dose for progressive pathogenesis, the reason for such is elusive. Here, we sought to investigate the mechanism of action of 3 mg/kg ICV-STZ on cognitive and non-cognitive aspects at a follow-up interval of 2 weeks for 2 months. On the 60th day, we examined the layer thickness, cell density, ventricular volume, spine density, protein expression related to brain metabolism, and mitochondrial function by histological examination. The findings suggest a progressive loss of a spatial, episodic, and avoidance memory with an increase in anxiety in a span of 2 months. Furthermore, hippocampal neurodegeneration, ventricular enlargement, diffused amyloid plaque deposition, loss of spine in the dentate gyrus, and imbalance in energy homeostasis were found on the 60th day post-injection. Interestingly, AD rats showed a uniform fraction of time spent in four quadrants of the water maze with a change in strategy when they were exposed to height. Our findings reveal that ICV-STZ injection at a dose of 3 mg/kg can cause cognitive and neuropsychiatric abnormalities due to structural loss both at the neuronal as well as the synaptic level, which is tightly associated with the change in neuronal metabolism.