Abstract
Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It is generally believed that β-amyloidogenesis, tau-hyperphosphorylation, and synaptic loss underlie cognitive decline in AD. Rps23rg1, a functional retroposed mouse gene, has been shown to reduce Alzheimer’s β-amyloid (Aβ) production and tau phosphorylation. In this study, we have identified its human homolog, and demonstrated that RPS23RG1 regulates synaptic plasticity, thus counteracting Aβ oligomer (oAβ)-induced cognitive deficits in mice. The level of RPS23RG1 mRNA is significantly lower in the brains of AD compared to non-AD patients, suggesting its potential role in the pathogenesis of the disease. Similar to its mouse counterpart, human RPS23RG1 interacts with adenylate cyclase, activating PKA/CREB, and inhibiting GSK-3. Furthermore, we show that human RPS23RG1 promotes synaptic plasticity and offsets oAβ-induced synaptic loss in a PKA-dependent manner in cultured primary neurons. Overexpression of Rps23rg1 in transgenic mice consistently prevented oAβ-induced PKA inactivation, synaptic deficits, suppression of long-term potentiation, and cognitive impairment as compared to wild type littermates. Our study demonstrates that RPS23RG1 may reduce the occurrence of key elements of AD pathology and enhance synaptic functions to counteract oAβ-induced synaptic and cognitive deficits in AD.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia in the elderly and is characterized pathologically by the extracellular deposition of β -amyloid (Aβ ) peptides and intracellular tangles comprising phosphorylated tau proteins[1,2]
We found that protein kinase A (PKA) activity was significantly enhanced in brain tissue lysates from Rps/V mice compared to with vehicle (WT/V) mice, and oAβ -induced PKA inactivation was significantly reduced in Rps23rg1 transgenic mice injected with oAβ s (Rps/Aβ) mice compared to with oAβ s (WT/Aβ) mice (Fig. 7C)
We have identified and characterized the human homolog of mouse Rps23rg[1], which was previously identified with the ability to reduce Aβ production and tau phosphorylation
Summary
Alzheimer’s disease (AD) is the most common form of dementia in the elderly and is characterized pathologically by the extracellular deposition of β -amyloid (Aβ ) peptides and intracellular tangles comprising phosphorylated tau proteins[1,2]. Activation of cyclic AMP (cAMP)-dependent protein kinase A (PKA) is generally important for synaptic function and learning and memory[9], and plays a seminal role in Aβ -associated synaptic loss and memory deficits. Such as GSK-3α /β have been implicated to drive AD pathogenesis, as their activities are aberrantly upregulated in AD patients and animal models[19,20]. We further demonstrated that exogenous expression of RPS23RG1 increased synapse numbers to offset oAβ -induced synaptic loss in a PKA-dependent manner in cultured neurons. Transgenic overexpression of mouse Rps23rg[1] in vivo restored PKA activity, and mitigated oAβ -induced synaptic loss, long-term potentiation (LTP) suppression, and cognitive impairment. Our results strongly suggest that upregulating RPS23RG1 and its downstream pathways may be a potential therapeutic approach for treating AD
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