P3‐123: Altered Peripheral Monocyte Innate Phagocytosis in Alzheimer’s Disease

Abstract

Background: 7, 8-Dihydroxyflavone (7, 8-DHF) has recently been identified as a high affinity tropomyosin receptor kinase B (TrkB) agonist, which mimic BDNF's neurotrophic signaling and overcome the pharmacokinetic and side effect barriers. Our recent work suggest that 7, 8-DHF is able to bind and activate TrkB, and rescue BDNF deficits in Alzheimer's disease (AD), the most common form of dementia in elderly adults, and Fragile X syndrome (FXS), the most common form of inherited intellectual disability. Methods: We synthesized pharmacologic, behavioral, and biochemical approaches to examine the effects of 7,8-DHF on spatial and fear memory functions, and morphological spine abnormalities in fragile X mental retardation 1 (Fmr1) gene knock-out mice and Tg2576 AD mice. Results: We found a large positive effect from 7, 8-DHF on learning and memory in fragile X mental retardation 1 (Fmr1) gene knock-out mice and the Tg2576 AD mouse model. A long term treatment with 7, 8-DHF improves spatial and fear learning and memory that depend on hippocampus and amygdala. 7, 8-DHF also ameliorates morphological spine abnormalities. Further mechanism analysis reveals that 7, 8-DHF increases the phosphorylation of TrkB and enhances synapse expression of GluA1 of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Potentially related to drug-induced changes in AMPA receptor subunits, 7, 8-DHF at the synapses leads to the phosphorylation of (i) specific serine sites including Ser818 and Ser813 of GluA1, and Ser880 of GluA2, and (ii) calcium/calmodulin-dependent protein kinase II and protein kinase C, two kinases that target these sites. 7, 8-DHF activated the phosphorylation of TrkB receptors and its downstream signals including CaMKII, Akt, Erk1/2, and cAMP-response elementbinding protein. Conclusions: Collectively, our results demonstrated that 7, 8-DHF acted on TrkB and resolved learning and memory impairments in Fmr1 gene knock-out mice and amyloid precursor protein transgenic mice partially through improving synaptic structure and enhanced synaptic AMPARs. Thus our works provide a potential therapeutic tool for FXS and AD treatment. Background: PACAP is reduced the brains and cerebrospinal fluids of Alzheimer's disease (AD) patients (Han et al 2014 Neurology. 82(19):1724-8; Han et al 2015 JAMA Neurol. 72(3):333-9). PACAP reduced Ab-induced toxicity in primary cultured mouse neurons and the neuroprotective effects could be attributed to the mitochondrial function enhancement (Han et al 2014 Neurobiol Aging. 35 (9):2064-71). Furthermore in mouse brain, PACAP enhanced the production of sAPPa while decreased Ab species, suggesting a shift of the APP metabolism from beta-secretase predominant pathway to alpha-secretase predominant pathway (Rat et al 2011.FASEB J.25 (9):3208-18.). However, the effect of PACAP on beta-secretase activity was not measured; the effects of PACAP on other key factors in AD pathogenesis had never been elucidated. In this study, we tested