Abstract
Many neurodegenerative diseases are characterized by the conformational change of normal self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high β-sheet content and resistance to degradation. The most common is Alzheimer's disease (AD) where the normal soluble amyloid β (sAβ) peptide is converted into highly toxic oligomeric Aβ and fibrillar Aβ that deposits as neuritic plaques and congophilic angiopathy. Currently, there is no highly effective treatment for AD, but immunotherapy is emerging as a potential disease modifying intervention. A major problem with most active and passive immunization approaches for AD is that both the normal sAβ and pathogenic forms are equally targeted with the potential of autoimmune inflammation. In order to avoid this pitfall, we have developed a novel immunomodulatory method that specifically targets the pathological conformations, by immunizing with polymerized British amyloidosis (pABri) related peptide which has no sequence homology to Aβ or other human proteins. We show that the pABri peptide through conformational mimicry induces a humoral immune response not only to the toxic Aβ in APP/PS1 AD transgenic mice but also to paired helical filaments as shown on AD human tissue samples. Treated APP/PS1 mice had a cognitive benefit compared to controls (p<0.0001), associated with a reduction in the amyloid burden (p = 0.0001) and Aβ40/42 levels, as well as reduced Aβ oligomer levels. This type of immunomodulation has the potential to be a universal β-sheet disrupter, which could be useful for the prevention or treatment of a wide range of neurodegenerative diseases.
Highlights
The diagnostic neuropathological lesions of Alzheimer’s disease (AD) are the accumulation of amyloid b (Ab) as neuritic plaques and congophilic angiopathy, as well as aggregation of abnormally phosphorylated tau in the form of neurofibrillary tangles (NFTs) [1]
In the present study we demonstrate for the first time that immunization in an AD Tg mouse model with a foreign peptide in a polymerized, b-sheet rich form is able through conformational mimicry to induce an immune response to both Ab42 and PHF
This immune response is associated with a strong behavioral rescue in the treated Tg mice as they performed similar to wild type mice in the radial arm maze
Summary
The diagnostic neuropathological lesions of AD are the accumulation of amyloid b (Ab) as neuritic plaques and congophilic angiopathy, as well as aggregation of abnormally phosphorylated tau in the form of neurofibrillary tangles (NFTs) [1]. AD is the most common of the neurodegenerative protein conformational disorders, which include diffuse Lewy body disease (DLBD), Parkinson’s disease (PD), prion diseases, and frontotemporal lobar degeneration (FTLD). In each of these disorders a normal self-protein/peptide, which has a physiological function, undergoes a conformational change to a pathological conformer that has a high b-sheet content, is resistant to degradation and accumulates either in extracellular plaques or intracellular inclusion bodies, with the most toxic conformers being oligomeric [2]. Among patients with a clinical diagnosis of dementia, neuropathological examination reveals that in a majority of cases there is an accumulation of a mixture of different pathological protein conformers, with the most common mix being Ab, phosphorylated tau and a-synuclein [4]. A major disadvantage to passive immunization for chronic neurodegenerative disorders would be the need for multiple infusions and the risk of developing anti-idiotypic immunity, which would limit efficacy and be associated with toxicity
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