Vaccine Development to Treat Alzheimer’s Disease Neuropathology

A novel vaccine addressing the major hallmarks of Alzheimer’s disease (AD), senile plaque-like deposits of amyloid beta-protein (Aβ), neurofibrillary tangle-like structures, and glial proinflammatory cytokines, has been developed. The present vaccine takes a new approach to circumvent failures of previous ones tested in mice and humans, including the Elan-Wyeth vaccine (AN1792), which caused massive T-cell activation, resulting in a meningoencephalitis-like reaction. The EB101 vaccine consists of Aβ1-4 2delivered in a novel immunogen-adjuvant composed of liposomes-containing sphingosine-1-phosphate (S1P). EB101 was administered to APPswe/PS1dE9 transgenic mice before and after AD-like pathological symptoms were detectable. Treatment with EB101 results in a marked reduction of Aβ plaque burden, decrease of neurofibrillary tangle-like structure density, and attenuation of astrocytosis. In this transgenic mouse model, EB101 reduces the basal immunological interaction between the T cells and immune activation markers in the affected hippocampal/cortical areas, consistent with decreased amyloidosis-induced inflammation. Therefore, immunization with EB101 prevents and reverses AD-like neuropathology in a significant manner by halting disease progression without developing behavioral spatial deficits in transgenic mice.

Alzheimer’s disease (AD) is the most frequent form of dementia in developed countries, with a prevalence of about 1% at the age of 65 and over 25% in people older than 85 years of age. Clinically, it is characterized by progressive cognitive deterioration, behavioral disturbances, and functional decline. It is known that AD is a polygenic/complex disorder in which hundreds of genes, distributed across the human genome, might be involved in close cooperation with environmental inducers, cerebrovascular dysfunction, and epigenetic phenomena [1]. The main neuropathological hallmarks of AD include accumulation of amyloid-β (Aβ) peptide, neurofibrillary tangle-like structures (NFTs) composed largely of paired helical filaments with phosphorylated tau proteins, neuronal and synaptic loss [2], reduced overall brain volume with specific damage of entorhinal cortex and hippocampus [3], neuroinflammation, gliosis, free radical formation [4], neurotransmitter and neurotrophic factor deficits, metabolic impairment [5], and proteasome and chaperone dysregulation [6]. In the past decade, Aβ-based immunotherapy has been shown to be the most promising therapeutic approach [712], and there are over 10,000 patients currently enrolled in active or passive Aβ immunotherapy, showing so far a certain degree of success in decreasing beta amyloid [1317] and reversing memory deficits [1820]. However, the first clinical trial in 2001 sponsored by Elan and Wyeth with active immunization, consisting of aggregated synthetic Aβ42 peptide delivered in QS21 adjuvant, resulted in 6% patient death due to a meningoencephalitis-like reaction [1321], probably induced by an over-extensive T-cell-mediated immune response [2223]. Remarkably, patients with abbreviated treatment generated anti-Aβantibodies, reducing cerebrospinal levels of tau and reported a slower cognitive decline [2425]. Prior to clinical trials, numerous experimental therapeutic immunization strategies were developed using transgenic mice models of AD-like pathology, including APPswe/PS1dE9 double transgenic mice, to investigate emergent therapies focused on preventing and/or treating AD neuropathology [2627]. Transgenic mice expressing mutated forms of the gene for the human amyloid precursor protein (hAPP) prematurely show marked elevation of Aβ-protein levels and deposition in the cerebral cortex and hippocampus [2830], as seen in the brain of AD patients [31]. Presenilin-1 (PS1-) mutant transgenic mice also show an increase in Aβ1-4 2 (Aβ42) peptide generation, potentiating amyloid deposition in the brain at about 6 months of age [32]. In the present study we used APPswe/PS1dE9 double-transgenic mice derived from the coexpression of mutated APP and PS1 genes, which have demonstrated a prematurely accelerated accumulation of Aβ deposits in the brain, compared with those expressing singly APP or PS1 mutations alone [3337]. This feature, together with a variety of other clinically relevant AD-like alterations, points out this model as a valuable tool in the development of new AD therapeutic approaches [38]. In the present study, we present the EB101 vaccine, which is designed to become cost-effective and long-lasting, being targeted toward the reduction of Aβ burden and the slowing of the main AD-like pathological alterations, including the inflammatory reaction, by the induction of an anti-inflammatory T-helper (Th) 2 immune response. All these requirements will be achieved by designing a physiological adjuvant composed of naturally occurring phospholipids, proven safe and efficacious in other type of vaccines, including influenza, with an added biologically active phospholipid, S1P, known to stimulate an anti-inflammatory reaction and act as a neuronal regenerating agent in in vitro and in vivo studies [39].

The purpose of this study was to investigate the effect and safety of an Aβ vaccine (EB101) in APPswe/PS1dE9 transgenic mice elicited by a novel immunogenic adjuvant, designed to reduce Aβdeposition but avoiding the massive activation of T-cell-mediated immune response that potentially caused severe adverse effects.

Reference (full-text): Iván Carrera, Ignacio Etcheverría, Lucía Fernández-Novoa, Valter Lombardi, Ramón Cacabelos, and Carmen Vigo, “Vaccine Development to Treat Alzheimer’s Disease Neuropathology in APP/PS1 Transgenic Mice,” International Journal of Alzheimer’s Disease, vol. 2012, Article ID 376138, 17 pages, 2012. doi:10.1155/2012/376138

Source: International Journal of Alzheimer’s Disease, 17/january/2013


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