LMP2 Inhibitors as a Potential Treatment for Alzheimer’s Disease

The
immunoproteasome (iP), an inducible proteasome variant harboring
three immunosubunits, low molecular mass polypeptide-2 (LMP2), multicatalytic
endopeptidase complex subunit-1, and low molecular mass polypeptide-7
(LMP7), is involved in multiple facets of inflammatory responses.
We recently reported that YU102, a dual inhibitor of the iP subunit
LMP2 and the constitutive proteasome catalytic subunit β1, ameliorates
cognitive impairments in mouse models of Alzheimer’s disease
(AD) independently of amyloid deposits. To investigate whether inhibition
of LMP2 is sufficient to improve the cognitive functions of AD mice,
here we prepared 37 YU102 analogues and identified a potent LMP2 inhibitor
DB-310 (28) (IC50: 80.6 nM) with improved
selectivity and permeability in cells overexpressing ABCB1 transporters.
We show that DB-310 induces suppression of IL-1α production
in microglia cells and improves cognitive functions in the Tg2576
transgenic mouse model of AD. This study supports that inhibition
of LMP2 is a promising therapeutic strategy for treatment of AD.