Brain-Derived Neurotrophic Factor (BDNF) Preserves the Functional Integrity of Neural Networks in the β-Amyloidopathy Model in vitro

Abstract

Alzheimer’s disease (AD) is a widespread chronic neurodegenerative pathology characterized by synaptic dysfunction, partial neuronal death, cognitive decline and memory impairments. The major hallmarks of AD are extracellular senile amyloid plaques formed by various types of amyloid proteins (Aβ) and the formation and accumulation of intracellular neurofibrillary tangles. However, there is a lack of relevant experimental models for studying changes in neural network activity, the features of intercellular signaling or the effects of drugs on the functional activity of nervous cells during AD development. In this work, we examined two experimental models of amyloidopathy using primary hippocampal cultures. The first model involves the embryonic brains of 5xFAD mice; the second uses chronic application of amyloid beta 1-42 (Aβ1-42). The model based on primary hippocampal cells obtained from 5xFAD mice demonstrated changes in spontaneous network calcium activity characterized by a decrease in the number of cells exhibiting Ca 2+ activity, a decrease in the number of Ca 2+ oscillations and an increase in the duration of Ca 2+ events from day 21 of culture development in vitro . Chronic application of Aβ1-42 resulted in the rapid establishment of significant neurodegenerative changes in primary hippocampal cultures, leading to marked impairments in neural network calcium activity and increased cell death. Using this model and multielectrode arrays, we studied the influence of amyloidopathy on spontaneous bioelectrical neural network activity in primary hippocampal cultures. It was shown that chronic Aβ application decreased the number of network bursts and spikes in a burst. The spatial structure of neural networks was also disturbed that characterized by reduction in both the number of key network elements (hubs) and connections between network elements. Moreover, application of brain-derived neurotrophic factor (BDNF) recombinant protein and BDNF hyperexpression by an adeno-associated virus vector partially prevented these amyloidopathy-induced neurodegenerative phenomena. BDNF maintained cell viability and spontaneous bioelectrical and calcium network activity in primary hippocampal cultures.

Exercise Rehabilitation and/or Astragaloside Attenuate Amyloid-beta Pathology by Reversing BDNF/TrkB Signaling Deficits and Mitochondrial Dysfunction

“…The increasing of BDNF in the brain with viruses [30,31] or transplanted cells [32][33][34] results in marked neuroprotective effects in several animal models of AD. In our results, ER and/or AST application might attenuate neurobehavior disorders and neurodegeneration in Ab-microinjected rats by preserving neuronal networks' BDNF-mediated functional integrity [35].…”

SIRT1-Dependent Upregulation of BDNF in Human Microglia Challenged with Aβ: An Early but Transient Response Rescued by Melatonin

“…In agreement, BDNF reduction has been largely linked to cognitive decline in AD patients [ 57 , 58 , 59 ] and preclinical in vivo models, where its administration proved to be neuro- and synapto-protective [ 60 , 61 , 62 ]. In vitro models provided concordant observations [ 63 , 64 , 65 ]. Notably, it was also shown that aging itself can cause a decline in microglial BDNF, which correlates with a pro-inflammatory switch [ 66 ].…”

Overexpression of Brain- and Glial Cell Line-Derived Neurotrophic Factors Is Neuroprotective in an Animal Model of Acute Hypobaric Hypoxia

“…Indeed, a number of studies have shown that recombinant neurotrophic factors are highly effective in models of various pathologies, including cerebral ischemia and neurodegenerative diseases, both in vitro and in vivo [ 25 , 26 , 34 , 35 , 36 ]. However, many methodological difficulties, including overcoming the blood–brain barrier and the short period of active molecules’ degradation, call into question the potential use of BDNF and GDNF in clinical practice.…”