Amyloid-β is an anti-microbial peptide, a component of the innate immune system. In the brain it is best known for increasing with age, misfolding, and then aggregating into toxic deposits. The presence of these aggregrates is thought to be the initial cause of Alzheimer’s disease, eventually inducing the late stage mechanisms of neuroinflammation and tau aggregation that kill neurons and ultimately kill the patient. On its own, it seems likely that amyloid-β aggregation is capable of producing only mild cognitive impairment. Nonetheless, amyloid-β remains the primary target of research and development for the treatment of Alzheimer’s disease.
Amyloid-β doesn’t only exist in the brain. The body and the brain are separated by the blood-brain barrier that polices which molecules can pass, and in what amounts. Amyloid-β can move between body and brain via the blood-brain barrier, and the amounts of amyloid-β on the two sides exist in a state of dynamic equilibrium. Researchers have demonstrated that clearing amyloid-β from the vasculature can encourage its exit from the brain, and that approach has reached fairly late stages of clinical development. Separately, amyloid-β should be cleared from the brain via the various pathways that drain cerebrospinal fluid – the glymphatic system and the cribriform plate, both of which become dysfunctional with age. A few research and development programs are focused on restoring flow via one path or another; Leucadia Therapeutics is nearing clinical trials for their approach.
Today’s open access paper reports a novel approach to draining amyloid-β from the brain via the blood-brain barrier, by upregulating the mechanisms involved in the normal export process. The fine details are somewhat complex, but involve adjusting the balance of materials presented for uptake to blood-brain barrier cells in order to prevent the cell from downregulating the expression and recycling of the LRP1 receptor used to take up amyloid-β. Cells tend to constantly shift levels of receptors used for uptake in response to circumstances, and downregulation of frequently used receptors is a common outcome that acts to prevent runaway uptake of any specific molecule. It is possible to confuse the underlying regulatory processes inside the cell by delivering carefully crafted materials that are taken up via other pathways, however.
The blood-brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer’s disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques.
We present a novel therapeutic strategy that targets low-density lipoprotein receptor-related protein 1 (LRP1) on the BBB. Our design leverages the multivalent nature and precise size of LRP1-targeted polymersomes to modulate receptor-mediated transport, biasing LRP1 trafficking toward transcytosis and thereby upregulating its expression to promote efficient Aβ removal.
In AD model mice, this intervention significantly reduced brain Aβ levels by nearly 45% and increased plasma Aβ levels by 8-fold within 2 hours, as measured by ELISA. Multiple imaging techniques confirmed the reduction in brain Aβ signals after treatment. Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory, with performance levels comparable to those of wild-type mice. These cognitive benefits persisted for up to 6 months post-treatment.
This work pioneers a new paradigm in drug design, where function arises from the supramolecular nature of the nanomedicine, harnessing multivalency to elicit biological action at the membrane trafficking level. Our findings also reaffirm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions significantly more effective. We establish a compelling case for BBB modulation and LRP1-mediated Aβ clearance as a transformative foundation for future AD therapies.
