According to the current paradigm, the main cause of AD is the accumulation of neurotoxic
amyloid beta (Aβ) peptide aggregates resulting from the cleavage of the amyloid precursor protein into
peptides of different length, with the 42 amino acid long Aβ42 being the most toxic form. Aβ can aggregate
and form plaques in the brain. It further promotes the hyperphosphorylation of the tau protein
which forms characteristic neurofibrillary tangles and thereby loses its important role in axonal transport
and contributes to neurodegeneration. Therefore, treatments have targeted Aβ, but clinical trials of immunotherapies
caused severe side effects and showed that Aβ clearance alone did not result in any cognitive improvement. This leads to
the question: what else promotes AD pathology? Here, we review data on systemic inflammation and the possible roles
that the immune system might play in AD. Microglia and astrocytes are activated and secrete inflammatory cytokines and
chemokines. Via a disturbed blood-brain barrier, peripheral immune cells are activated and recruited towards inflamed
brain lesions and amyloid plaques, but due to the chronic nature of the amyloid burden and their reduced function, these
cells are not able to control inflammation and the associated detrimental immune responses. In addition, age-related inflammation
and chronic infection with herpes viruses might contribute to the systemic inflammation and exacerbate attempts
to restore the balance of inflammation.
Keywords: Alzheimer Disease, CMV, HSV, immunity, Inflammation, leukocytes, T-cell differentiation.
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