The progressive accumulation of amyloid-beta
(Aβ) in specific
areas of the brain is a common prelude to late-onset of Alzheimer’s
disease (AD). Although activation of liver X receptors (LXR) with
agonists decreases Aβ levels and ameliorates contextual memory
deficit, concomitant hypercholesterolemia/hypertriglyceridemia limits
their clinical application. DMHCA (
N
,
N
-dimethyl-3β-hydroxycholenamide) is an LXR partial agonist
that, despite inducing the expression of apolipoprotein E (main responsible
of Aβ drainage from the brain) without increasing cholesterol/triglyceride
levels, shows nil activity
in vivo
because of a low
solubility and inability to cross the blood brain barrier. Herein,
we describe a polymer therapeutic for the delivery of DMHCA. The covalent
incorporation of DMHCA into a PEG-dendritic scaffold via carboxylate
esters produces an amphiphilic copolymer that efficiently self-assembles
into nanometric micelles that exert a biological effect in primary
cultures of the central nervous system (CNS) and experimental animals
using the intranasal route. After CNS biodistribution and effective
doses of DMHCA micelles were determined in nontransgenic mice, a transgenic
AD-like mouse model of cerebral amyloidosis was treated with the micelles
for 21 days. The benefits of the treatment included prevention of
memory deterioration and a significant reduction of hippocampal Aβ
oligomers without affecting plasma lipid levels. These results represent
a proof of principle for further clinical developments of DMHCA delivery
systems.
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