Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

Abstract

Previously, we reported that Alzheimer's disease (AD) epitope vaccines (EVs) composed of N-terminal b-amyloid (Ab 42 ) B cell epitope fused with universal foreign T helper (Th) epitope(s) were immunogenic, potent, and safe in different amyloid precursor protein (APP) transgenic mice with early AD-like pathology. However, developing an effective therapeutic vaccine is much more challenging, especially when a self-antigen such as Ab 42 is a target. Here, we directly compare the efficacy of anti-Ab 42 antibodies in Tg2576 mice with low or high levels of AD-like pathology at the start of immunizations: 6-6.5 months for preventive vaccinations and 16-19 months for therapeutic vaccinations. EV in a preventive setting induced high levels of anti-Ab antibodies, significantly reducing pathologic forms of Ab in the brains of Tg2576 mice. When used therapeutically for immunesenescent Tg2576 mice, EV induced low levels of antibodies not sufficient for clearing of AD-like pathology. Separately, we demonstrated that EV was also not effective in 11-11.5-month-old Tg2576 mice with moderate AD-like pathology. However, we augmented the titers of anti-Ab antibodies in transgenic (Tg) mice of the same age possessing the pre-existing memory Th cells and detected a significant decrease in diffuse and core plaques in cortical regions compared to control animals along with improved novel object recognition performance. INTRODUCTIONA critical goal of developing therapeutic interventions for Alzheimer's disease (AD) has been the identification of suitable targets. During the last two decades, the predominant theory of the etiology of AD was that Ab has a central role in the onset and progression of AD, as delineated in the amyloid cascade hypothesis. 1,2 According to this hypothesis, the accumulation of Ab peptide, either by overproduction or aberrant clearance, results in deposition of Ab in plaques, which leads to the formation of neurofibrillary tau tangles and cell death, resulting in dementia. Later on, the amyloid cascade hypothesis evolved to focus on oligomers and protofibrils of Ab as instigators in the destruction of synaptic function. [3][4][5] Support for the amyloid cascade hypothesis was spurred by the identification of mutations in amyloid precursor protein (APP) that are associated with familial AD 6-8 or protection against amyloid pathology and age-related Alzheimer's disease. [9][10][11] In addition, it was discovered that overexpression of APP due to trisomy 21 in Downs disease was associated with a high incidence of AD in these individuals. [12][13][14] Today it is clear that the pathological tau also plays a vital role in the development of AD pathology and progression of this disease, 15 correlating better with the degree of dementia than Ab plaques. Importantly, substantial data suggest that Ab pathology emerges many years prior to tau pathology and accelerates formation of toxic tau aggregates, [16][17][18] supporting the preventive rather than therapeutic potential of anti-amyloid therapies.Immunotherapies target...

Yeast-Based Aβ1-15 Vaccine Elicits Strong Immunogenicity and Attenuates Neuropathology and Cognitive Deficits in Alzheimer’s Disease Transgenic Mice

“…The Aβ accumulation and accompanying neuronal loss have been corroborated in the previous studies [ 30 , 31 ]. To assess whether the reduction of Aβ accumulation can attenuate synaptic deficits, we used anti-synaptophysin antibody to detect the effect of Y-5A15 yeast vaccine on the synapses.…”

A MultiTEP platform-based epitope vaccine targeting the phosphatase activating domain (PAD) of tau: therapeutic efficacy in PS19 mice

“…To study how the immunization with AV-1980R/A affects cognition, PS19 mice were also tested in novel object recognition (NOR) and novel place recognition (NPR) paradigms, which rely on cortical and hippocampal function respectively, both areas strongly affected by AD pathology 44–46 . This analysis demonstrated that vaccination of PS19 mice with AV-1980R/A resulted in a significant increase in the exploration of a non-familiar object as indicated by the increased discrimination index compared with mice injected with adjuvant only ( p < 0.01 ; Fig.…”

“…Novel object and novel place recognition tests were used to evaluate cognition as previously described 46,77 . All combinations of locations and objects were balanced across trials to eliminate bias.…”

Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice

“…The MultiTEP strategy provides a unique opportunity to generate high levels of antibodies in the elderly by activating not only naïve Th cells, but also pre-existing memory Th cells previously generated in response to infections and/or vaccinations with tetanus toxin, hepatitis B, and influenza, thereby overcoming immunosenescence. Indeed, the feasibility of this strategy based on pre-existing memory Th cells was previously demonstrated [10, 21, 44].…”

“…Earlier, we demonstrated that in mice and monkeys, AV-1959 induced antibodies specific to the AEFRH epitope of Aβ 1–11 peptide incorporated in this vaccine [41]. This immunodominant B cell epitope of N-terminus of Aβ 42 [45] is widely used in preclinical and clinical studies, and data from various groups, including us, suggest that high-affinity antibodies specific to this region reduce AD-like pathology not only in mouse models of AD but also in brains of vaccinated people [18, 20, 21, 25, 44, 46–51]. Immunizations with AV-1959R/A also induced therapeutically potent antibodies that significantly reduced soluble and insoluble Aβ 42 pathology in this pathologically aggressive bigenic mouse model of AD (Fig.…”