Neuritic Beading Induced by Activated Microglia Is an Early Feature of Neuronal Dysfunction Toward Neuronal Death by Inhibition of Mitochondrial Respiration and Axonal Transport

Abstract

Recent studies suggest that excitotoxicity may contribute to neuronal damage in neurodegenerative diseases including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. Activated microglia have been observed around degenerative neurons in these diseases, and they are thought to act as effector cells in the degeneration of neural cells in the central nervous system. Neuritic beading, focal bead-like swellings in the dendrites and axons, is a neuropathological sign in epilepsy, trauma, ischemia, aging, and neurodegenerative diseases. Previous reports showed that neuritic beading is induced by various stimuli including glutamate or nitric oxide and is a neuronal response to harmful stimuli. However, the precise physiologic significance of neuritic beading is unclear. We provide evidence that neuritic beading induced by activated microglia is a feature of neuronal cell dysfunction toward neuronal death, and the neurotoxicity of activated microglia is mediated through N-methyl-D-aspartate (NMDA) receptor signaling. Neuritic beading occurred concordant with a rapid drop in intracellular ATP levels and preceded neuronal death. The actual neurite beads consisted of collapsed cytoskeletal proteins and motor proteins arising from impaired neuronal transport secondary to cellular energy loss. The drop in intracellular ATP levels was because of the inhibition of mitochondrial respiratory chain complex IV activity downstream of NMDA receptor signaling. Blockage of NMDA receptors nearly completely abrogated mitochondrial dysfunction and neurotoxicity. Thus, neuritic beading induced by activated microglia occurs through NMDA receptor signaling and represents neuronal cell dysfunction preceding neuronal death. Blockage of NMDA receptors may be an effective therapeutic approach for neurodegenerative diseases.

Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

“…In backcrossing and extensively interbreeding DJ-1-null mice, we obtained a subset of DJ1-C57 mice that exhibited robust unilateral nigral degeneration as early as 8 wk of age: a finding potentially consistent with the early-onset pathogenicity of DJ-1 loss in human carriers of DJ-1 mutations (1). This cell loss was accompanied with compensatory sprouting and the appearance of dysmorphic and beading neurites, as well as microgliosis, a result congruent with the notion that microglia may induce neuritic beading during neuronal dysfunction (24). Furthermore, findings of compensatory sprouting upon cell loss, dysmorphic neurites, and an increase in proinflammatory responses are all present in postmortem samples from PD patients (25)(26)(27)(28)(29)(30).…”

Measurement of saturation processes in glutamatergic and GABAergic synapse densities during long-term development of cultured rat cortical networks

“…Cortices of 2 rats were dissociated into single cells using dissociation solution (Sumitomo Bakelite Co.), then resuspended in Neuron Culture Medium (serum-free conditioned medium from 48-h rat astrocyte confluent cultures based on Dulbecco's modified Eagle's medium [DMEM]/F-12 with N2 supplement; Sumitomo Bakelite; Takeuchi et al, 2005). The cell suspension was plated onto poly(ethyleneimine)-coated 13φ coverslips, which were inserted into 24-well cell culture plates at a density of 250 cells/mm 2 for immunofluorescence staining.…”

Mitochondrial Dysfunction and Dendritic Beading during Neuronal Toxicity

“…4) Dendritic beading has been proposed to correlate with a drop in cytoplasmic [ATP] (5,19), although the earliest time points examined were 1 (5) or 6 h (19). Using a cytoplasmic luciferase reporter construct (17) to monitor cytoplasmic [ATP], we observed a rapid depletion of ATP within the time scale (15 min) of dendritic beading (Fig.…”

“…Although Ca 2ϩ -induced excitotoxicty and Na ϩ -induced dendritic beading appear to be distinct, both processes are activated simultaneously by excitotoxic stimuli. Indeed, NMDA receptors are permeable to both ions and are implicated in both processes (5,6), yet the spatial and temporal relationship between these events have not been examined.…”