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Background and Objectives: Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes cognitive impairment. The Aim of this Study: Was to evaluate microvesicles (MVs) and melatonin effects on mitochondrial biogenesis and apoptosis in an experimental model of Alzheimer's disease in rats Methods: Forty-five female rats were divided randomly (9 rats in each group) intoGpI (control) and experimental groups, which included: GpII (AD), GpIII (AD+MVs), GpIV (AD+melatonin), GpV (AD+MVs+melatonin). Induction of AD was done by a single intraperitoneali.p injection of lipopolysaccharide (LPS) of 0.8mg/kg. One week after the AD induction, the treated groups received a single i.p injection of MVs at a dose of 0.2mg/kg or melatonin by i.p injection of 10mg/kg once daily for three weeks or combined therapy of both. When the experiment was over, Y-maze & open field tests were used to assess the cognitive functions. The hippocampus was subjected to histological and immunohistochemical studies for assessment of the morphological changes. Besides, biochemical investigations were performed for AD pathogenesis, mitochondrial biogenesis, inflammatory mediators, and apoptosis. Results: The AD modeling group demonstrated impaired cognitive function, a significant increase in AD markers; Aβ plaques deposition in Congo-red stained sections and the levels of Aβ-42 and p-tau protein, increased apoptotic markers; Casp-3 positive immunostaining and Cyt-c level, a significant reduction in mitochondrial biogenesis markers; gene expressions of PGC-1α, Nrf-2, TFAM and Sirt-1, affection of the brain energy metabolism represented by the AMPK level. Besides, the IL-6 level increased significantly. The therapy with MVs, melatonin, or combined therapy had a curative role against AD with the best results in the combined therapy group. Conclusion: Combined therapy with MVs and melatonin was superior to single therapy for AD. [ABSTRACT FROM AUTHOR]