Abstract
Alzheimer’s disease (AD) is the most common cause of dementia, and currently, there is no effective treatment. The major neuropathological lesions in AD are accumulation of amyloid β (Aβ) as amyloid plaques and congophilic amyloid angiopathy, as well as aggregated tau in the form of neurofibrillary tangles (NFTs). In addition, inflammation and microglia/macrophage function play an important role in AD pathogenesis. We have hypothesized that stimulation of the innate immune system via Toll-like receptor 9 (TLR9) agonists, such as type B CpG oligodeoxynucleotides (ODNs), might be an effective way to ameliorate AD related pathology. We have previously shown in the Tg2576 AD model that CpG ODN can reduce amyloid deposition and prevent cognitive deficits. In the present study, we used the 3xTg-AD mice with both Aβ and tau related pathology. The mice were divided into 2 groups treated from 7 to 20 months of age, prior to onset of pathology and from 11 to 18 months of age, when pathology is already present. We demonstrated that immunomodulatory treatment with CpG ODN reduces both Aβ and tau pathologies, as well as levels of toxic oligomers, in the absence of any apparent inflammatory toxicity, in both animal groups. This pathology reduction is associated with a cognitive rescue in the 3xTg-AD mice. Our data indicate that modulation of microglial function via TLR9 stimulation is effective at ameliorating all the cardinal AD related pathologies in an AD mouse model mice suggesting such an approach would have a greater chance of achieving clinical efficacy.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia globally [1]
The importance of inflammatory pathways affecting the function of microglia for the pathogenesis of AD is highlighted by the results of genome-wide association studies (GWAS), where many of the implicated genes have a major role in immunological processes, as well as the recent linkage to AD of a rare variant of TREM2, a gene that regulates phagocytosis and the activation state of microglia/macrophages [5,6]
Post hoc analysis revealed that the Wt mice traveled more distance, moved at a faster speed, and rested less than CpG ODN-treated Tg mice or Tg controls in the 7–20 month study group
Summary
Alzheimer’s disease (AD) is the most common cause of dementia globally [1]. AD is characterized by the presence of amyloid β (Aβ) deposits in forms of parenchymal amyloid plaques and congophilic amyloid angiopathy (CAA), as well as aggregated tau protein in the form of neurofibrillary tangles (NFTs). The most toxic species of aggregated Aβ and tau are thought to be oligomeric [2]. Inflammation is another feature of AD pathology, which is linked to the production of cytokines by activated microglia. The importance of inflammatory pathways affecting the function of microglia for the pathogenesis of AD is highlighted by the results of genome-wide association studies (GWAS), where many of the implicated genes have a major role in immunological processes, as well as the recent linkage to AD of a rare variant of TREM2, a gene that regulates phagocytosis and the activation state of microglia/macrophages [5,6]. Microglia play a critical role in the innate immune system of the CNS and one of the most potent ways to stimulate this system is via the Toll-like receptors (TLRs)
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