LRP1 at the crossroads of Parkinson's and Alzheimer's: Divergent roles in α-synuclein and amyloid pathology.

PMID 40484331 | DOI 10.1016/j.ejphar.2025.177830 · European journal of pharmacology · 2025

Parkinson's disease (PD) is the second most common neurodegenerative disease that represents the commonest movement disorder in the elderly population. PD neuropathology is due to the progressive deposition of mutant alpha synuclein (α-Syn) in the dopaminergic neurons (DNs) of the substantia nigra pars compacta (SNpc). Additionally, amyloid protein (Aβ) and tau protein, which are the hallmarks of Alzheimer's disease (AD), are also involved in PD and the development of PD-related dementia. Notably, α-Syn, Aβ, tau protein, and neuronal cholesterol metabolism are regulated by a transmembrane protein, low-density lipoprotein receptor-related protein 1 (LRP1), which is highly expressed in the SNpc and mediates the transmission and seeding of α-Syn in the brain. It has been reported that deletion of the LRP1 gene protects against the development and progression of PD. However, LRP1 has a neuroprotective effect against AD neuropathology by improving Aβ clearance across the blood-brain barrier (BBB) and enhancing tau protein proteolysis. Nevertheless, the exact role of LRP1 in PD neuropathology, mostly about α-Syn, is not completely explained. Therefore, this review aims to discuss and explain the role of LRP1 in PD and how targeting neuronal LRP1 may be helpful in the management of PD. In this review, online databases were involved by searching Scopus, Web of Science, and other search engine to detect the relationship between the expression of LRP1 and the pathogenesis of PD.