Alzheimer's disease (AD) is a neurodegenerative disorder that is remarkably characterized by pathological hallmarks which include amyloid plaques, neurofibrillary tangles, neuronal loss, and progressive cognitive loss. Several well-known genetic mutations which are being used for the development of a transgenic model of AD lead to an early onset familial AD (fAD)-like condition. However, these settings are only reasons for a small percentage of the total AD cases. The large majorities of AD cases are considered as a sporadic in origin and are less influenced by a single mutation of a gene. The etiology of sporadic Alzheimer's disease (sAD) remains unclear, but numerous risk factors have been identified that increase the chance of developing AD. Among these risk factors are insulin desensitization/resistance state, oxidative stress, neuroinflammation, synapse dysfunction, tau hyperphosphorylation, and deposition of Aβ in the brain. Subsequently, these risk factors lead to development of sAD. However, the underlying molecular mechanism is not so clear. Streptozotocin (STZ) produces similar characteristic pathology of sAD such as altered glucose metabolism, insulin signaling, synaptic dysfunction, protein kinases such as protein kinase B/C, glycogen synthase-3β (GSK-3β) activation, tau hyperphosphorylation, Aβ deposition, and neuronal apoptosis. Further, STZ also leads to inhibition of Akt/PKB, insulin receptor (IR) signaling molecule, and insulin resistance in brain. These alterations mediated by STZ can be used to explore the underlying molecular and pathophysiological mechanism of AD (especially sAD) and their therapeutic intervention for drug development against AD pathology.

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Rational Inhibition of renin-angiotensin system (RAS) improves cognitive functions in hypertensive patients. However, role of AT1 and AT2 receptors in memory impairment due to cholinergic hypofunction is unexplored. Objective This study investigated the role of AT1 and AT2 receptors in cerebral blood flow (CBF), cholinergic neurotransmission, and cerebral energy metabolism in scopolamineinduced amnesic mice. Methods Scopolamine was given to male Swiss albino mice to induce memory impairment tested in passive avoidance and Morris water maze tests after a weeklong administration of blocker of AT1 receptor, candesartan, and AT2 receptor, PD123, 319. CBF was measured by laser Doppler flowmetry. Biochemical and molecular studies were done in cortex and hippocampus of mice brain. Results Scopolamine caused memory impairment, reduced CBF, acetylcholine (ACh) level, elevated acetylcholinesterase (AChE) activity, and malondialdehyde (MDA). Administration of vehicle had no significant effect on any parameter in comparison to control. Candesartan prevented scopolamineinduced amnesia, restored CBF and ACh level, and decreased AChE activity and MDA level. In contrast, PD123, 319 was not effective. However, the effect of AT1 receptor blocker on memory, CBF, ACh level, and oxidative stress was blunted by concomitant blockade of AT2 receptor. Angiotensin-converting enzyme (ACE) activity, ATP level, and mRNA expression of AT1, AT2, and ACE remained unaltered. Conclusion The study suggests that activation of AT1 receptors appears to be involved in the scopolamine-induced amnesia and that AT2 receptors contribute to the beneficial effects of candesartan. Theses finding corroborated the number of clinical studies that RAS inhibition in hypertensive patients could be neuroprotective.