The D-serine biosynthetic enzyme serine racemase is expressed by reactive astrocytes in the amygdala of human and a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is characterized behaviorally by cognitive deterioration and emotional disruption, and neuropathologically by amyloid-β (A β) plaques, neurofibrillary tangles, and complement C3 (C3)-expressing neurotoxic, reactive astrocytes. We previously demonstrated that C3 + reactive astrocytes in the hippocampus and entorhinal cortex of AD patients express serine racemase (SR), which produces the N-methyl-D-aspartate receptor (NMDAR) co-agonist D-serine. We show here that C3 + reactive astrocytes express SR in the amygdala of AD patients and in an amyloid mouse model of familial AD (5xFAD). 5xFAD mice also have deficits in cue fear memory recall that is dependent on intact amygdala function. Our results suggest that D-serine produced by reactive astrocytes in the amygdala could contribute to glutamate excitotoxicity and neurodegeneration observed with AD progression.