Peripherally restricted PICK1 inhibitor mPD5 ameliorates pain behaviors in murine inflammatory and neuropathic pain models.

Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting 1 in 5 adults. Current treatment is compromised by dose-limiting side effects, including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions.

Cholinergic neurodegeneration and cholesterol metabolism dysregulation by constitutive p75 signaling in the p75-KO mice.

Degeneration of basal forebrain cholinergic neurons (BFCNs) is a hallmark of Alzheimer's disease (AD). However, few mouse models of AD recapitulate the neurodegeneration of the cholinergic system. The p75 neurotrophin receptor, p75, has been associated with the degeneration of BFCNs in AD.

Detection of endogenous NPY release determined by novel GRAB sensor in cultured cortical neurons.

Neuropeptide Y (NPY) is an abundantly expressed peptide in the nervous system. Its widespread distribution along with its receptors, both centrally and peripherally, indicates its broad functions in numerous biological processes. However, the low endogenous concentration and diffuse distribution of NPY make it challenging to study its actions and dynamics directly and comprehensively.

Expression of an alternatively spliced variant of SORL1 in neuronal dendrites is decreased in patients with Alzheimer's disease.

SORL1 is strongly associated with both sporadic and familial forms of Alzheimer's disease (AD), but a lack of information about alternatively spliced transcripts currently limits our understanding of the role of SORL1 in AD. Here, we describe a SORL1 transcript (SORL1-38b) characterized by inclusion of a novel exon (E38b) that encodes a truncated protein. We identified E38b-containing transcripts in several brain regions, with the highest expression in the cerebellum and showed that SORL1-38b is largely located in neuronal dendrites, which is in contrast to the somatic distribution of transcripts encoding the full-length SORLA protein (SORL1-fl).

TrkA-mediated endocytosis of p75-CTF prevents cholinergic neuron death upon γ-secretase inhibition.

γ-secretase inhibitors (GSI) were developed to reduce the generation of Aβ peptide to find new Alzheimer's disease treatments. Clinical trials on Alzheimer's disease patients, however, showed several side effects that worsened the cognitive symptoms of the treated patients. The observed side effects were partially attributed to Notch signaling.