Abstract
Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aβ) peptides in the Alzheimer’s brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. The ability for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, to export Aβ across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp–Aβ interaction persist. Here, molecular data affirm that both Aβ40 and Aβ42 peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the inhibition of Aβ42 transport in brain capillaries from P-gp-knockout mice. Moreover, we explored whether P-gp could exert the same role in neurons. Comparison between non-neuronal CHO-APP and human neuroblastoma SK-N-SH cells revealed that P-gp is expressed and active in both cell types. Inhibiting P-gp activity using verapamil and nicardipine impaired Aβ40 and Aβ42 secretion from both cell types, as determined by ELISA. Collectively, these findings implicate P-gp in Aβ export from neurons, as well as across the BBB endothelium, and suggest that restoring or enhancing P-gp function could be a viable therapeutic approach for removing excess Aβ out of the brain in Alzheimer’s disease.
Highlights
The accumulation of amyloid-beta (Aβ) peptides in the brain is a key pathological hallmark of Alzheimer’s disease (AD)
Verapamil yielded as physiological ratios observed in human AD brains [52,66]
Aβ peptide suggests that simple diffusion, as it has until now been assumed, does not adequately explain the mechanism of its expulsion into the extracellular space
Summary
The accumulation of amyloid-beta (Aβ) peptides in the brain is a key pathological hallmark of Alzheimer’s disease (AD). Aβ40 and the more hydrophobic and aggregation-prone Aβ42 are the most common isoforms, with a higher ratio of Aβ42 : Aβ40 being associated with increased neurotoxicity, and accelerated disease pathology and cognitive decline [2]. In the brain, these peptides are constitutively produced in neurons and astrocytes following enzymatic cleavage of the transmembrane amyloid precursor protein (APP), and subsequently rapidly cleared [3,4,5]. Excess levels of soluble oligomeric Aβ have been demonstrated to impair long-term potentiation, drive synaptic and receptor dysfunction, propagate tau pathology, neuroinflammation, and oxidative stress, and correlate with disease severity [7,8,9]
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