Neurology Central

Immunotherapy for mild cognitive impairment patients: a role for omega-3 fatty acids in improving innate immunity against amyloid-beta

Despite over 200 clinical trials, as of yet no drug for Alzheimer’s disease (AD) has been approved, but the search continues for a successful candidate, in particular  for the early stage of AD, mild cognitive impairment (MCI). Recent trials of amyloid-beta (Aβ) antibodies have failed in the search for a blockbuster medication. The antibody approach to enhancing microglial phagocytosis of Aβ (1–42) was developed in mutant amyloid-precursor protein transgenic mouse models. These models were not constructed with the human immune system and therefore did not reproduce the innate immune defects of AD patients. The studies in animal models have produced conflicting results regarding the role of brain microglia and peripheral monocytes. The microglia are poorly phagocytic for Aβ in comparison to peripheral monocytes, and monocytes do not clear Aβ after repopulation of the mouse brain. An example of this lack of translation between mouse models and clinical results is exhibited in the therapeutic use of the antineoplastic agent bexaroten, which was made headlines when it lowered Aβ in animal models [1], yet these findings did not translate into human patients [2].

Our breakthrough discovery of defective phagocytosis of Aβ by monocyte/macrophages of AD patients suggested a new immunotherapeutic approach through enhancement of innate immunity [3]. This approach has been even more compelling because we found that peripheral blood mononuclear cells (PBMCs) of AD patients downregulated N-acetylglucosamine transferase  when exposed to Aβ, probably accounting in part for the defective macrophage phenotype  [4]. Thus, we think that the deregulation of the innate immune system in AD and MCI patients may account for poor brain clearance and needs to be repaired first before treatment with antibody therapies. 

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