Clearance of peripheral amyloid-β
(Aβ) has been demonstrated
to be promising for overcoming the blood–brain barrier (BBB)
hurdle to eliminate brain-derived Aβ associated with Alzheimer’s
disease (AD). Even so, current developed therapeutic assays for clearance
of peripheral Aβ are still facing challenges on how to avoid
interference of certain biological molecules and prevent triggering
the activation of immune responses and blood clotting. Here, a biomimetic
nanozyme (Cu
x
O@EM-K) with augmented protein
adsorption resistance, minimized immunogenicity, and enhanced biocompatibility
is designed and synthesized. The Cu
x
O@EM-K
is made of Cu
x
O nanozyme wrapped with
modified 3xTg-AD mouse erythrocyte membrane with Aβ-targeting
pentapeptide KLVFF. KLVFF serves as Aβ-specific ligand that
works together with erythrocyte membrane to selectively capture Aβ
in the blood. Meanwhile, the erythrocyte membrane coating prevents
protein coronas formation and thus retains Aβ-targeting ability
of Cu
x
O@EM-K in biological fluids. More
importantly, the Cu
x
O core with multiple
antioxidant enzyme-like activities stabilizes the outer erythrocyte
membrane and simultaneously mitigates Aβ-induced membrane oxidative
damage, which enables the extended systemic circulation indispensable
for adsorbing Aβ. In vivo studies demonstrate that Cu
x
O@EM-K not only reduces Aβ burden in the blood
and brain but also ameliorates memory deficits in the widely used
3xTg-AD mouse model. Moreover, Cu
x
O@EM-K
shows no apparent toxicity in 3xTg-AD mice. Overall, this work provides
an example for developing biocompatible and synergistic clearance
of peripheral Aβ associated with AD.
Phototherapy,
such as photodynamic therapy and photothermal therapy,
holds great potential for modulation of Alzheimer’s β-amyloid
(Aβ) self-assembly. Unfortunately, current works for phototherapy
of Alzheimer’s disease (AD) are just employing either visible
or first near-infrared (NIR-I) light with limited tissue penetration,
which can not avoid damaging nearby normal tissues of AD patients
through the dense skull and scalp. To overcome the shortcomings of
AD phototherapy, herein we report an amyloid targeting, N-doped three-dimensional
mesoporous carbon nanosphere (KD8@N-MCNs) as a second near-infrared
(NIR-II) PTT agent. This makes it possible for photothermal dissociation
of Aβ aggregates through the scalp and skull in a NIR-II window
without hurting nearby normal tissues. Besides,
KD8@N-MCNs have both superoxide dismutase and catalase activities,
which can scavenge intracellular superfluous reactive oxygen species
and alleviate neuroinflammation in vivo. Furthermore,
KD8@N-MCNs efficiently cross the blood–brain barrier owing
to the covalently grafted target peptides of KLVFFAED on the nanosphere
surface. In vivo studies demonstrate that KD8@N-MCNs
decrease Aβ deposits, ameliorate memory deficits, and alleviate
neuroinflammation in the 3xTg-AD mouse model. Our work provides a
biocompatible and non-invasive way to attenuate AD-associated pathology.
Alzheimer's disease (AD) is a progressive neurodegenerative disease which is clinically characterized by memory loss and cognitive decline caused by protein misfolding and aggregation. Imbalance between free radicals and the antioxidant system is a prominent and early feature in the neuropathology of AD. Selenium (Se), a vital trace element with excellent antioxidant potential, is preferentially retained in the brain in Se-limited conditions and has been reported to provide neuroprotection through resisting oxidative damage. In this paper, we studied for the first time the potential of Ebselen, a lipid-soluble selenium compound with GPx-like activity, in the treatment of cognitive dysfunction and neuropathology of triple-transgenic AD (3 × Tg-AD) mice, AD model cell, and primary culture. We demonstrated that Ebselen inhibited oxidative stress in both AD model cells and mouse brains with increasing GPx and SOD activities and meanwhile reduced p38 mitogen-activated protein kinases activities. By decreasing the expression of amyloid precursor protein and β-secretase, Ebselen reduced the levels of Aβ in AD neurons and mouse brains, especially the most toxic oligomeric form. Besides, mislocation of phosphorylated tau in neurons and phosphorylation levels of tau protein at Thr231, Ser396, and Ser404 residues were also inhibited by Ebselen, probably by its regulatory roles in glycogen synthase kinase 3β and protein phosphatase 2A activity. In addition, Ebselen mitigated the decrease of synaptic proteins including synaptophysin and postsynaptic density protein 95 in AD model cells and neurons. Consequently, the spatial learning and memory of 3 × Tg-AD mice were significantly improved upon Ebselen treatment. This study provides a potential novel therapeutic approach for the prevention of AD.
The N-terminus of hCTR1 was demonstrated to bind three Cu(+) ions tightly (log K = 14.92) and reversibly via its Met-rich motifs. Ag(+) binds to the protein with the same stoichiometry but much lower affinities than Cu(+). The protein also coordinates two Cu(2+) ions through its ATCUN motif and His-rich motif with lower affinity. This study provides an insight into the selectivity of the transporter.
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