Brain-derived neurotrophic factor and TrkB expression in the “oldest-old,” the 90+ Study: correlation with cognitive status and levels of soluble amyloid-beta

Abstract

Factors associated with maintaining good cognition into old age are unclear. Decreased brain-derived neurotrophic factor (BDNF) contributes to memory loss in Alzheimer's disease (AD), and soluble assemblies of amyloid-beta (Aβ) and tau contribute to neurodegeneration. However, it is unknown whether AD-type neuropathology, soluble Aβ and tau, or levels of BDNF and its receptor TrkB correlate with dementia in the oldest-old. We examined these targets in post-mortem Brodmann's areas 7 and 9 (BA7, BA9) in 4 groups of subjects >90 years old: 1) No Dementia/No AD Pathology, 2) No Dementia/AD Pathology, 3) Dementia/No AD Pathology, 4) Dementia/AD Pathology. In BA7, BDNF mRNA correlated with MMSE scores and was decreased in demented vs. non-demented subjects, regardless of pathology. Soluble Aβ42 was increased in both groups with AD pathology, demented or not, compared to No dementia/No AD Pathology subjects. Groups did not differ in TrkB isoform levels or in levels of total soluble tau, individual tau isoforms, threonine-181 tau phosphorylation or ratio of phosphorylated 3R to 4R isoforms. In BA9, soluble Aβ42 correlated with MMSE scores and with BDNF mRNA expression. Thus, soluble Aβ42 and BDNF, but not TrkB or soluble tau, correlate with dementia in the oldest-old.

Brain‐derived neurotrophic factor of the cerebral microvasculature: a forgotten and nitric oxide‐dependent contributor of brain‐derived neurotrophic factor in the brain

“…For instance, BDNF val66met polymorphism affects both activity-dependent secretion of BDNF and human memory (Egan et al 2003). Likewise, low brain BDNF levels are largely suspected to be involved in the cognitive impairment associated with stress-related mood disorders (Duman & Monteggia 2006) and brain BDNF mRNA levels correlated with Mini-Mental State results in aged patients (Michalski et al 2015). On the basis of the commonly held belief that the neuron is the main cellular source of BDNF present in the brain, it is assumed that diseases associated with impaired cognition may benefit from therapeutic options that restore BDNF synthesis/ secretion by neurons.…”

Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

“…• A build up of toxic proteins in the brain (Lansbury et al, 2006;Majd et al, 2015;Zaltieri et al, 2015) • A loss of mitochondrial function that leads to the oxidative stress and creation of neurotoxic molecules that trigger cell death (apoptotic, necrotic or autophagy) Betarbet et al,2000;Zhu and Chu, 2010) • Changes in the levels and activities of neurotrophic factors (Zuccato and Cattaneo, 2009;Michalski et al, 2015) • Variations in the activity of neural networks Kann, 2015;Sala-Llonch et al, 2014).…”

“…Decreased level of neurotrophic factors: decreased levels and activities of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), have been described in a number of neurodegenerative disorders, including Huntington disease, Alzheimer's disease and Parkinson's disease (Zuccato and Cattaneo, 2009;Michalski et al, 2015)). These studies have led to the development of experimental strategies aimed at increasing BDNF levels in the brains of animals that have been genetically altered to mimic neurodegenerative human diseases, with a view to ultimately influencing the clinical treatment of these conditions.…”

Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: Correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer's disease

“…Several independent research laboratories, including our group, posit that deficiencies in neurotrophic activity leads to selective vulnerability of specific neuronal populations, whereas gain of neurotrophic function may facilitate recovery by targeting mechanisms of neuroplasticity (Mufson, Counts, Fahnestock, & Ginsberg, 2007a;Mufson et al, 2007bMufson et al, ,2015Nagahara et al, 2009). Previous regional postmortem human brain studies have shown that Bdnf, a complex transcript with multiple isoforms, is decreased in cortex, hippocampus, and basal forebrain in end stage AD (Alvarez, Aleixandre, Linares, Masliah, & Moessler, 2014;Garzon, Yu, & Fahnestock, 2002;Holsinger, Schnarr, Henry, Castelo, & Fahnestock, 2000;Michalski, Corrada, Kawas, & Fahnestock, 2015;Murray, Gall, Jones, & Isackson, 1994;Phillips et al, 1991). In contrast, Ngf levels have not shown marked differences in AD cortex (Fahnestock, Scott, Jette, Weingartner, & Crutcher, 1996;Jette, Cole, & Fahnestock, 1994;Mufson et al, 2003).…”

“…Previous regional postmortem human brain studies have shown that Bdnf , a complex transcript with multiple isoforms, is decreased in cortex, hippocampus, and basal forebrain in end stage AD (Alvarez, Aleixandre, Linares, Masliah, & Moessler, ; Garzon, Yu, & Fahnestock, ; Holsinger, Schnarr, Henry, Castelo, & Fahnestock, ; Michalski, Corrada, Kawas, & Fahnestock, ; Murray, Gall, Jones, & Isackson, ; Phillips et al, ). In contrast, Ngf levels have not shown marked differences in AD cortex (Fahnestock, Scott, Jette, Weingartner, & Crutcher, ; Jette, Cole, & Fahnestock, ; Mufson et al, ).…”