Alzheimer’s disease: Peripheral administration of 6H4 antibody fragments in polymeric nanomicelles reduces various toxic Aβ species in the brain

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Researchers from Japan have found a way to ensure that new medications are delivered to the right place in the body and at the right timepoint in disease progression, so that they have the best effect.

In a study published recently in the Journal of Nanobiotechnology, researchers led by Tokyo Medical and Dental University (TMDU) have revealed that a novel delivery system delivers treatment to where it is needed most in a mouse model of Alzheimer’s disease (AD).

Original Research: Open access.
Peripheral administration of nanomicelle-encapsulated anti-Aβ oligomer fragment antibody reduces various toxic Aβ species in the brain” by Takanori Yokota et al. Journal of Nanobiotechnology

Alzheimer’s disease (AD) is the most common neurodegenerative disease that causes dementia; it is characterized pathologically by extraneural deposition of amyloid β (Aβ) continually cleaved from an amyloid precursor protein by β- and γ-secretase activities in the central nervous system.

Growing evidence has shown that synaptic dysfunction associated with extraneural Aβ oligomers (AβOs) in the brains of patients with AD is one of the main toxic agents in the early stages of AD pathology [1]. Recently, the following newly identified toxic Aβ species have been reported: intraneural AβO [2], which is inversely correlated with synaptic density [3]; toxic Aβ conformers [4], which have a turn structure at positions 22–23 associated with rapid oligomerization, neurotoxicity, and synaptotoxicity; pyroglutamated Aβ (N3pE Aβ) [5, 6], amino-terminally truncated and pyroglutamate-modified Aβ with exceptionally high amyloidogenicity, proteolytic resistance, neurotoxicity, and accelerating senile plaque formation with other Aβ species.

These toxic Aβ species cooperatively participate in the pathophysiology of AD, causing a cognitive decline in collaboration with abnormally phosphorylated tau proteins [7].

However, anti-Aβ therapy trials, including anti-AβO therapies and aducanumab, have never achieved satisfactory efficacy in humans [8, 9].

Possible reasons for these unsatisfactory results include the following:

(1) inability of antibodies to selectively act against disease-specific targets in the brain,

(2) presence of multiple targets involving various forms of Aβ,

(3) relatively late administration of antibodies,

(4) side effects (such as amyloid-related imaging abnormalities [ARIA; ARIA-E: suggestive of vasogenic edema and sulcal effusions, ARIA-H: suggestive of hemosiderin deposits]),

(5) extremely low permeability of the blood–brain barrier (BBB) to the movement of full-body antibodies from the blood vessels into the brain.

It is well known that delivering high molecular weight compounds, including full-body antibodies, into the brain is difficult [10] because only small molecules less than approximately 500 Da can pass through the BBB [11]. To resolve the difficulty of trans-BBB migration, we recently developed a peripheral intravenous administration of glucosylated polymeric nanomicelles (PMs) via glucose transporters in vascular endothelial cells and were successful in demonstrating that PMs that are more than 56 times larger compared with conventional methods can pass through the BBB [12].

Moreover, this technology was adopted for the anti-Aβ antibody 3D6 (Bapineuzumab) fragment (Fab), and the anti-Aβ antibody fragments (Fabs) encapsulated in the PMs effectively inhibited Aβ deposition and reduced neurotoxicity in the brains of young AD model mice [13].

Next, the anti-AβO antibody 6H4, which is compatible with the previously reported monoclonal anti-AβO antibody 72D9 [14], was newly generated. The antibody has specificity for the structure of AβO conformation although not the amino-acid sequence of Aβ. The antibody recognizes pentamers, trimers, and high-molecular-weight oligomeric polymers of Aβ.

Interestingly, the Fabs maintained the same sensitivity and specificity to the AβO structure. To evaluate the efficacy of 6H4 Fabs encapsulated in the PMs on AD pathology, we evaluated the quantitative and histochemical changes of these toxic Aβ species after long-term peripheral administration of anti-AβO 6H4 Fabs encapsulated in the PMs in AD model mice at the age of amyloid plaque deposition in the brain. We also aimed to determine the cognitive function of these mice using a behavioral analysis.

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