Antagonism of a key peptide 'T14' driving neurodegeneration: Evaluation of a next generation therapeutic.

T14, a 14mer peptide derived from the C-terminus of acetylcholinesterase (AChE) is a signalling molecule that could drive neurodegeneration via the alpha 7 nicotinic acetylcholine receptor. Its levels increase as Alzheimer's pathology progresses; however, a cyclic variant of the compound, NBP14, can block the effects of the endogenous linear counterpart in-vitro, ex vivo, and in vivo. Here, we explore the antagonistic potential of two 6mer peptides, NBP6A and NBP6B. These are smaller linear versions of NBP14, designed to be more effective by modifying the amino acid residues to enhance receptor blockade alongside other relevant solubility parameters. The peptides were tested in-vitro in PC12 cells on three parameters, calcium influx, cell viability, and AChE release, and ex vivo using voltage sensitive dye imaging (VSDI) in rat brain slices. Neither NBP6A nor NBP6B applied alone had any effect. In PC12 cells, NBP6B was identified as the more potent molecule since it demonstrated more effective blockade of T14 action on calcium influx, cell viability, and AChE release. NBP6B was then further evaluated using VSDI, where it proved twice as potent as NBP14 in blocking the action of T14. The improved effect of NBP6B in blocking the actions of T14, combined with its smaller size suggests that this variant could have even greater therapeutic potential than its original cyclic compound, for treating neurodegenerative disorders.

Diversity in striatal synaptic circuits arises from distinct embryonic progenitor pools in the ventral telencephalon.

Synaptic circuits in the brain are precisely organized, but the processes that govern this precision are poorly understood. Here, we explore how distinct embryonic neural progenitor pools in the lateral ganglionic eminence contribute to neuronal diversity and synaptic circuit connectivity in the mouse striatum. In utero labeling of Tα1-expressing apical intermediate progenitors (aIP), as well as other progenitors (OP), reveals that both progenitors generate direct and indirect pathway spiny projection neurons (SPNs) with similar electrophysiological and anatomical properties and are intermingled in medial striatum. Subsequent optogenetic circuit-mapping experiments demonstrate that progenitor origin significantly impacts long-range excitatory input strength, with medial prefrontal cortex preferentially driving aIP-derived SPNs and visual cortex preferentially driving OP-derived SPNs. In contrast, the strength of local inhibitory inputs among SPNs is controlled by birthdate rather than progenitor origin. Combined, these results demonstrate distinct roles for embryonic progenitor origin in shaping neuronal and circuit properties of the postnatal striatum.

The perception of three-dimensional cast-shadow structure is dependent on visual awareness.

In the present study we examined whether the perception of depth from cast shadows is dependent on visual awareness using continuous flash suppression (CFS). As a direct measure of how the visual system infers depth from cast shadows, we examined the cast-shadow motion illusion originally reported by Kersten, Knill, Mamassian, and Bulthoff (1996), in which a moving cast shadow induces illusory motion in depth in a physically stationary object. In Experiment 1, we used a disparity defined probe to determine the stereo motion speed required to match the cast-shadow motion illusion for different cast shadow speeds (0°/s-1.6°/s) and different lighting directions. We found that configurations implying light from above produce more compelling illusory effects. We also found that increasing shadow speed monotonically increased the stereo motion speed required to match the illusory motion, which suggests that quantitative depth can be derived from cast shadows when they are in motion. In Experiment 2, we used CFS to suppress the cast shadow from visual awareness. Visual suppression of the cast shadow from awareness greatly diminished the perception of illusory motion in depth. In Experiment 3 we confirmed that while CFS suppresses the cast-shadow motion from awareness, it continues to be processed by the visual system sufficient to generate a significant motion after effect. The results of the present study suggest that cast shadows can greatly contribute to the perception of scene depth structure, through a process that is dependent on the conscious awareness of the cast shadow.