BDNF-trkB signaling in late life cognitive decline and Alzheimer’s disease

Abstract

AbstractExpression levels of BDNF and trkB, primary components of an important neurotrophin signaling pathway, have been reported to be abnormal in neurodegenerative dementias. Here, we used a novel postmortem brain tissue stimulation paradigm to examine BDNF-induced trkB signaling in participants of the Religious Orders Study, a large longitudinal clinicopathological study of aging and cognition. Thawed slices of anterior cingulate cortex were incubated in BDNF and changes in phosphorylated trkB and downstream signaling molecules ERK2 and Akt were measured, as well as the association of NMDA receptors with trkB. We found that stimulation with BDNF induced much greater activity of the BDNF-trkB signaling pathway in brain tissues of people with cognitive decline and AD, as evidenced by significantly more phosphorylation of trkB (pY-trkB), ERK2 (pY/pT-ERK2), Akt (pS-Akt), and greater BDNF-induced coupling of trKB with NMDAR2A/B. These findings were independent of PHFtau neurofibrillary tangle and amyloid-b plaque densities and other potentially confounding variables. Regression analyses with clinical features further characterized significant relationships between measures of BDNF-trkB activation and domains of cognition and emotional functioning. Increased BDNF-trkB signaling with cognitive decline could reflect a primary derangement of pathway functioning or a compensatory neuroplastic response to counteract neural injury associated with neurodegenerative processes.