Immunocytochemical Characterization of Alzheimer Disease Hallmarks in APP/PS1 Transgenic Mice Treated with a New Anti-Amyloid-βVaccine

Abstract

APP/PS1 double-transgenic mouse models of Alzheimer's disease (AD), which overexpress mutated forms of the gene for human amyloid precursor protein (APP) and presenilin 1 (PS1), have provided robust neuropathological hallmarks of AD-like pattern at early ages. This study characterizes immunocytochemical patterns of AD mouse brain as a model for human AD treated with the EB101 vaccine. In this novel vaccine, a new approach has been taken to circumvent past failures by judiciously selecting an adjuvant consisting of a physiological matrix embedded in liposomes, composed of naturally occurring phospholipids (phosphatidylcholine, phosphatidylglycerol, and cholesterol). Our findings showed that administration of amyloid-β 1−42 (Aβ) and sphingosine-1-phosphate emulsified in liposome complex (EB101) to APP/PS1 mice before onset of Aβ deposition (7 weeks of age) and/or at an older age (35 weeks of age) is effective in halting the progression and clearing the AD-like neuropathological hallmarks. Passive immunization with EB101 did not activate inflammatory responses from the immune system and astrocytes. Consistent with a decreased inflammatory background, the basal immunological interaction between the T cells and the affected areas (hippocampus) in the brain of treated mice was notably reduced. These results demonstrate that immunization with EB101 vaccine prevents and attenuates AD neuropathology in this type of double-transgenic mice.

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

“…84,85 Although the scope of this review is on liposome-strategies with the aim of facilitating BBB crossing, it is important to mention that other strategies have been developed for the use of liposomes for AD treatment. 89,[113][114][115][116] Curcumin is a natural compound extract from the plant Curcuma longa, and has been reported to be a fluorescent molecule with high affinity for the Aβ peptide and able to reduce Aβ aggregation. In this way, intracranial injection of liposomes encapsulating curcumin efficiently labeled Aβ deposits in both human and mice tissues, proving to be an effective formulation for diagnosis and treatment of AD.…”

“…113 Also, intraperitoneal injection of liposomes containing phosphatidic acid or cardiolipin was able to reduce Aβ peptides in the plasma and shifted the equilibrium that exists between brain and blood Aβ peptides, slightly affecting the plaques in the brain. 89 Lastly, different liposome-based vaccines were developed and directed toward Aβ plaques 115,116 and tau.…”

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

“…Among these, APP/PS1 double transgenic mice are an extensively used model, showing progressive age-related development of Aβ accumulation and cognitive deficits (Jankowsky et al 2001;Trinchese et al 2004;van Groen et al 2006;Meyer-Luehmann et al 2009;Filali et al 2011;Janus et al 2015). Furthermore, previous studies have revealed positive results, such as demonstrating various antioxidants (Garcia-Alloza et al 2010;Varamini et al 2014;Yanagisawa et al 2015), neuroprotective agents (Kilgore et al 2010;Peng et al 2012;Li et al 2014), anti-neuroinflammation (Cherry et al 2015;Guo et al 2015), immune therapy (Sudduth et al 2013;Carrera et al 2013;Zhang et al 2015), and nonpharmacological interventions (Liu et al 2011;Jankowsky et al 2005), which can attenuate or even reserve AD-like pathology in APP/PS1 mice. Unfortunately, none of these potentially useful results have been able to be reproduced in clinical therapies for AD patients.…”

Targeted Nanoparticles for the Treatment of Alzheimer's Disease

“…However, the clinical trial had to be interrupted because of a significant number of meningoencephalitis among the immunized subjects probably induced by an extensive T-cell-mediated immune response [202]. In order to overcome this problem, Carrera et al developed a system (EB101) consisting of A 1−42 and sphingosine-1-phosphate emulsified in a phospholipid liposome complex [203][204][205]. Monthly intraperitoneal administration (9 injections, 7 months) of EB101 to APP/PS1 mice before the onset of A deposition and/or at an older age was effective in halting the progression and reducing the AD-like neuropathological hallmarks: A plaques, neurofibrillary tangle-like structures, activated astrocytes, and neuroinflammation.…”