Reduced p75^NTRexpression delays disease onset only in female mice of a transgenic model of familial amyotrophic lateral sclerosis

Abstract

hSOD1 (G93A) transgenic mice develop pathological changes similar to those in patients with familial amyotrophic lateral sclerosis (FALS). In particular, the progressive degeneration of motoneurons is charactered in this mouse model. One feature of stressed motoneurons in ALS and the hSOD1 mice is the induction of the p75 neurotrophin receptor, which is thought, under certain circumstances, to be a death-signaling molecule. We have studied disease progression of hSOD1 (G93A) mice in the absence of the p75NTR receptor and we monitored histological changes in the ventral spinal cord. Whereas female double transgenics showed prolonged survival, this effect was not observed in males. Improved survival in female mice was not correlated with increased motoneuronal survival, but with less astrocytic activation in lumbar ventral spinal cord, as shown by glial fibrillary acidic protein immunohistochemistry. These data suggest that p75NTR is not directly involved in the mechanism leading to motoneuron degeneration. More likely, an indirect process, presumably via regulation of astrocytes, might be responsible for the increased survival responses of female double transgenic mice.

Epicatechin blocks pro-nerve growth factor (proNGF)-mediated retinal neurodegeneration via inhibition of p75 neurotrophin receptor proNGF expression in a rat model of diabetes

“…A critical role of p75 NTR , a member of the TNF superfamily, in mediating neuronal death has been documented in models of neurodegenerative diseases, including diabetes [47][48][49]. In agreement, our results showed that diabetes stimulates p38MAPK phosphorylation and cleaved PARP in vivo, and that high glucose stimulates p75 NTR and NTR using siRNA blocked these effects in NG and HG media (n=3).…”

Retrograde apoptotic signaling by the p75 neurotrophin receptor

“…However, crossing the SOD1 G93A mice with p75 − / − mice provided only partial protection in females [79]. These results are complicated by the multifaceted role of the receptor in other cells that could affect motor neuron viability (e.g.…”

The proNGF-p75NTR-Sortilin Signalling Complex as New Target for the Therapeutic Treatment of Parkinsons Disease

“…Reductions in p75NTR expression and subsequent caspase activation in spinal cord were consistent with increased neuronal survival in antisense nucleic acid-treated mice, indicating that p75NTR might be a promising target for antisense nucleic acid treatment. Reduced p75NTR expression also delayed disease onset in a transgenic hSOD1 (G93A) mouse model of ALS, and increased motoneuronal survival correlated with less astrocytic activation in spinal cord [84]. In addition, a complete deletion of p75NTR resulted in long-lasting increases in the number of basal forebrain cholinergic neurons in p75NTR gene knockout mice [21].…”