Immunology and immunotherapy of Alzheimer's disease

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Alzheimer's disease affects more than 20 million people worldwide and is characterized by progressive memory deficits, cognitive impairment and personality changes. It is believed that the main cause of Alzheimer's disease is increased production and accumulation of amyloid-β peptide (amyloid-β1–42). Although inflammation had not been viewed as a hallmark of Alzheimer's disease, amyloid-β deposition activates a potentially pathological innate immune response, including complement, microglial-cell activation and astrocyte proliferation. There is a reduced prevalence of Alzheimer's disease among chronic users of non-steroidal anti-inflammatory drugs (NSAIDs). This might be due to the effects of NSAIDs on the protease that generates amyloid-β1–42 from amyloid precursor protein rather than to anti-inflammatory effects. Immunotherapy in mouse models of Alzheimer's disease by active immunization of amyloid-β or by passive administration of amyloid-β-specific antibodies markedly reduces amyloid-β levels in the brain and reverses behavioural impairment. A human clinical trial of amyloid-β immunization led to meningoencephalitis in some patients with Alzheimer's disease and was discontinued. Nevertheless, in a subset of the clinical trial participants, those with plaque-reactive amyloid-β-specific antibodies in the plasma had a significantly slower rate of cognitive decline than those patients that did not have detectable amyloid-β- specific antibodies. Microglial cells represent a natural mechanism by which protein aggregates and debris can be removed from the brain, and there are multiple routes by which resident microglial cells can be activated to promote clearance of amyloid-β. Evidence from animal models and patients with Alzheimer's disease indicates that microglial-cell activation can lead to amyloid-β clearance. Although there is no clear T-cell response in the brains of patients with Alzheimer's disease, understanding T-cell responses and adaptive immunity has become important in the immunotherapy of Alzheimer's disease. Induction of appropriate T-cell subsets might have a central role in non-antibody-mediated clearance of amyloid-β, most probably by stimulating microglial cells.