MORPHO-FUNCTIONAL EVALUATION OF 3MGlKG ICV-STZ RAT SHOWED SPORADIC ALZHEIMER'S LIKE PATHOLOGY WITH PROGRESSIVE DEMENTIA

Abstract Background Intracerebroventricular streptozotocin (ICV-STZ) injection is among the best animal models to simulate sporadic Alzheimer’s disease (sAD). Abnormality in brain insulin signalling, neurodegeneration, neuroinflammation, cholinergic damage, mitochondrial dysfunction, genetic abnormality, respiratory problem, oxidative stress, gliosis, sleep disturbances are associated with cognitive abnormalities seen in ICV-STZ injected rats. Available experimental evidence has used varying doses of STZ (<1 to 3mg/kg) and studied its effect for different study durations, ranging from 14-21 (short), 30-42 (mild), 90-105 (moderate) and 250-270 (long) days. These studies indicated that 3mg/kg of body-weight is the optimum dose for inducing sAD in the rodents. However, studies on the pathological process with related the morphological and functional abnormalities reported were illusive. Objective/Method Hence in the present study, we have investigated the morpho-functional changes after 3mg/kg ICV-STZ treatment with a follow-up of two months in 54 male Wistar rats (ethical no. 937/IAEC/PhD-2016). Results Exhibited a spatial, episodic and avoidance memory decline and increase in anxiety (p<0.05) in ICV-STZ group progressively with time from 15th day to 60th day post-injection. Morphometry showed hippocampal atrophy with CA1, CA3 layer thinning (p ≤0.01) and loss of neurons (p<0.0001) associated with third ventricular enlargement (p= 0.007) in ICV-STZ rats versus sham, along-with extracellular amyloid plaque in AD rats with Congored staining. In addition, spine morphometry with Golgi-Cox impregnation of mossy fibre showed a reduction of spine density in AD group versus control and sham group (p<0.0001). Finally, immunohistochemistry of GSK3ß, PI3K and mtCOX-1 antigen in coronal sections revealed an increase in mean intensity of GSK3ß and decrease in PI3K and mtCox-1 in brain areas associated with limbic system in ICV-STZ group on 60th day. Conclusion These findings suggest progressive dementia and anxiety in 3mg/kg STZ treated rats, which may be due to hippocampal atrophy, amyloidopathy, ventricular enlargement, synaptic dysfunction and deficits in energy homeostasis of brain.