Neuroscience
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Neurofilaments (NF) are released into the cerebrospinal fluid (CSF) during multiple sclerosis (MS), but their role outside the axon is still unknown. In vitro NF fractions, as well as tubulin (TUB), increase oligodendrocyte (OL) progenitor proliferation and/or their differentiation depending on the stage of their purification (Fressinaud et al., 2012). However the mechanism by which NF enter these cells, as well as that of synthetic peptides displaying NFL-tubulin-binding site (NFL-TBS.40-63) (Fressinaud and Eyer, 2014), remains elusive. ⋯ Clathrin-dependent endocytosis was further confirmed by treatment with dynasore, a dynamin inhibitor, which inhibited the uptake of peptides, as well as NFP2 fractions, by 50%. This study demonstrates that axon cytoskeletal proteins and peptides can be internalized by OL through endocytosis. This process could be involved during demyelination, and the release of axon proteins might promote remyelination.
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Basal forebrain cholinergic neurons (BFCN) are selectively vulnerable to damage and loss in a number of neurodegenerative disorders that afflict the elderly, particularly Alzheimer's disease. The reasons for this selective vulnerability remain poorly understood. Given that intraneuronal accumulation of the amyloid-β peptide (Aβ) has been shown to exert deleterious effects on neurons, we tested potential accumulation of Aβ within BFCN in rhesus monkeys, which like the human display age-related accumulation of this peptide in plaques. ⋯ In some nbM-Ch4 neurons, 1282 immunoreactivity had the appearance of large peptide aggregates. Significant accumulation and age-related increase of Aβ in BFCN is likely to interfere with the normal functioning of these neurons. It remains to be determined if similar accumulation of Aβ occurs in human BFCN.
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Previous results have shown that the substance P (SP) N-terminal fragment SP1-7 may attenuate hyperalgesia and produce anti-allodynia in animals using various experimental models for neuropathic pain. The heptapeptide was found to induce its effects through binding to and activating specific sites apart from any known neurokinin or opioid receptor. Furthermore, we have applied a medicinal chemistry program to develop lead compounds mimicking the effect of SP1-7. ⋯ The extensive target screen, including 111 targets, did not reveal any hit for the binding site among a number of known receptors or enzymes involved in pain modulation. Our animal studies confirmed that SP1-7, but also synthetic analogs thereof, possesses anti-allodynic effects in the mouse SNI model of neuropathic pain. One of the lead compounds, a constrained H-Phe-Phe-NH2 analog, was shown to exhibit a significant anti-allodynic effect.
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The rodent anterior cingulate cortex (ACC) is critical for visceral pain and pain-related aversive response in chronic visceral hypersensitive (VH) state. Long-term potentiation (LTP), induced by theta burst stimulation (TBS) in the medial thalamus (MT)-ACC pathway, is blocked in VH rats. However, the neuronal intrinsic firing characteristics and the MT-ACC connectivity have not been investigated in visceral pain. ⋯ Neural spike activity in the ACC becomes synchronized with ongoing theta oscillations of LFP. Furthermore, cross correlation analysis showed augmented synchronization of thalamo-ACC theta band LFPs, which was consistent with an increase of neuronal communication between the two regions. In conclusion, these results reveal theta oscillations and theta-frequency phase-locking as prominent features of neural activity in the ACC and a candidate neural mechanism underlying acute visceral pain.
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In Alzheimer's disease (AD), numerous β-amyloid (Aβ) plaques are associated with butyrylcholinesterase (BChE) activity, the significance of which is unclear. A mouse model, containing five human familial AD genes (5XFAD), also develops Aβ plaques with BChE activity. Knock-out of BChE in this model showed diminished fibrillar Aβ plaque deposition, more so in males than females. This suggests that lack of BChE reduces deposition of fibrillar Aβ in AD and this effect may be influenced by sex.