Activation of CB2 Receptor System Reverses Amyloid-Induced Memory Deficiency and Restores SOX2 Activity in a Transgenic Mouse Model of Alzheimer's Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory and cognitive function. The brains of patients with AD are characterized by extensive deposits of extracellular aggregation of amyloid-beta peptides. These peptides form senile plaques and intracellular aggregation of hyperphosphorylated tau protein. In addition, amyloid fibrils activate the inflammatory pathway, characterized by the activated microglia and astrocytes seen in the brains of patients with AD.

Cannabinoid type 2 (CB2) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in AD. CB2 receptors are upregulated in reactive microglial cells in AD. This upregulation of CB2 receptors tends to attenuate the activation of early pro-inflammatory microglial signaling pathways associated with AD.

Sox2 (sex-determining region Y (SRY)-box 2) is a transcriptional factor that is essential for maintaining self-renewal/proliferation of undifferentiated embryonic stem cells (ESCs) and multipotency of neural stem cells (NSCs). Sox2 behaves as a protective factor during the development of Alzheimer’s disease.

We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl)carbonyl) piperidine (MDA7) a novel, blood brain barrier-permeant, and highly selective CB2 agonist that lacks psychoactivity on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment in the Tg-APPsw/PSEN1DE9 (APP/PS1) mouse model of AD. APP/PS1 mice are well suited for our investigations because they exhibit high production of Aβ peptides in the brain, accumulation of amyloid plaques, and demonstrate cognitive impairments. Senile plaques can be detected by thioflavin S or 3D6 as early as 4 months of age, and there is an overall increase in plaque burden with age. PAPP/PS1 mice displayed significantly impaired glutamatergic long-term potentiation (LTP) in the hippocampal CA1 neurons, indicating an impaired synaptic plasticity. LTP is an experimental phenomenon that takes place at excitatory glutamatergic synapses and is believed to play a central role in learning and memory.

At 3 mo of age, MDA7 14 mg/kg was administered intraperitoneally (i.p.) every other day for 5 mo. Another cohort of APP/PS1 received i.p. injections of the vehicle at alternate days for 5 mo. In the APP/PS1 transgenic mice, compared to wild type mice, treatment with MDA7 (i) ameliorated the expression of Iba1 (microglia marker), (ii) promoted amyloid-beta clearance in the hippocampal CA1, (iii) restored the expression of SOX2 (stem cell marker) in the hippocampal dentate gyrus, and (iv) restored synaptic plasticity, cognition and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for Alzheimer’s disease.

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