Abstract
BackgroundAlzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder and characterized by progressive loss of memory and cognitive functions, which are associated with amyloid-beta (Aβ) plaques. Immune cells play an important role in the clearance of Aβ deposits. Immune responses are regulated by immune regulators in which the B7 family members play a crucial role. We have recently identified erythroid membrane-associated protein (ERMAP) as a novel B7 family-related immune regulator and shown that ERMAP protein affects T cell and macrophage functions.MethodsWe produced a monoclonal antibody (mAb) against ERMAP protein and then determined the ability of the mAb to affect cognitive performance and AD pathology in mice.Results We have shown that the anti-ERMAP mAb neutralizes the T cell inhibitory activity of ERMAP and enhances macrophages to phagocytose Aβ in vitro. Administration of the mAb into AD mice improves cognitive performance and reduces Aβ plaque load in the brain. This is related to increased proportion of T cells, especially IFNγ-producing T cells, in the spleen and the choroid plexus (CP), enhanced expression of immune cell trafficking molecules in the CP, and increased migration of monocyte-derived macrophages into the brain. Furthermore, the production of anti-Aβ antibodies in the serum and the macrophage phagocytosis of Aβ are enhanced in the anti-ERMAP mAb-treated AD mice.ConclusionsOur results suggest that manipulating the ERMAP pathway has the potential to provide a novel approach to treat AD patients.
Highlights
Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder and characterized by progressive loss of memory and cognitive functions, which are associated with amyloid-beta (Aβ) plaques
We show here that administration of the anti-erythroid membrane-associated protein (ERMAP) monoclonal antibody (mAb) increases the functions of both T cells and macrophages, resulting in reduced Aβ plaque load and improved cognitive performance in AD mice
Our results suggest that administration of anti-ERMAP mAb results in increased percentage of T cells, especially IFNγ-producing T cells in the spleen and the choroid plexus (CP), and enhanced CP activity
Summary
Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder and characterized by progressive loss of memory and cognitive functions, which are associated with amyloid-beta (Aβ) plaques. Immune cells play an important role in the clearance of Aβ deposits. We have recently identified erythroid membrane-associated protein (ERMAP) as a novel B7 family-related immune regulator and shown that ERMAP protein affects T cell and macrophage functions. The cognitive decline is related to hallmark protein aggregates, amyloid-β (Aβ) plaques and neurofibrillary tangles, which can accelerate neuronal cell death, adversely affect synaptic function and eventually cause neuron loss [1, 3,4,5,6,7]. Recognizing the importance of the B7 family in controlling immune responses, we performed a series of genome-wide database searches to find molecules that are homologous to known B7 family members. ERMAP protein inhibits T cell functions and increases the generation of anti-inflammatory M2 macrophages, whereas anti-ERMAP antibody neutralizes the T cell inhibitory activity of ERMAP and enhances macrophage phagocytosis ability [16]
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