Effects of sustained proNGF blockade on attentional capacities in aged rats with compromised cholinergic system

Abstract

Disruption in nerve growth factor (NGF) signaling via trkA receptors compromises the integrity of the basal forebrain (BF) cholinergic system, yielding cognitive, specifically attentional, impairments in Alzheimer’s disease (AD). Although normal aging is considered a risk factor for AD, the mechanisms underlying the selective vulnerability of the aging cholinergic system to trkA disruption is not clear. The levels of proNGF, a proneurotrophin that possesses higher affinity for p75 receptors, increase in aging. The present study was designed to test the hypothesis that cholinergic and attentional dysfunction in aged rats with reduced BF trkA receptors occurs due to the overactivation of endogenous proNGF signaling. We employed a viral vector that produced trkA shRNA to suppress trkA receptors in the corticopetal cholinergic neurons of aged rats. BF trkA suppression impaired animals’ performance on signal trials in both the sustained attention task (SAT) and the cognitively-taxing distractor version of SAT (dSAT) and these deficits were normalized by chronic intracerebroventricular administration of proNGF antibody. Moreover, depolarization-evoked ACh release and the density of cortical cholinergic fibers were partially restored in these animals. However, SAT/dSAT scores reflecting overall performance did not improve following proNGF blockade in trkA knockdown rats due to impaired performance in non-signal trials. Sustained proNGF blockade alone did not alter baseline attentional performance but produced moderate impairments during challenging conditions. Collectively, our findings indicate that barring proNGF-p75 signaling may exert some beneficial effects on attentional capacities specifically when BF trkA signaling is abrogated. However, endogenous proNGF may also possess neurotrophic effects and blockade of this proneurotrophin may not completely ameliorate attentional impairments in AD and potentially hinder performance during periods of high cognitive load in normal aging.

Interactions between Aβ oligomers and presynaptic cholinergic signaling: Age-dependent effects on attentional capacities

“…The capacity of prefrontal cholinergic synapses to produce phasic increases in cholinergic activity was probed by locally applying rapid potassium pulses [26, 28, 32]. As illustrated in Fig.…”

“…Stable criterion performance was characterized by signal duration-dependent hit rates, ≥ 70% hits to 500 ms signals, ≥70% correct rejections, and a relatively low number of omissions (<10% of all trials; equal distribution among trial types) for at least 3 consecutive sessions. At this stage, animals were exposed to a distractor session (dSAT) that involved the presentation of distractors (flashing house light @ 0.5 Hz) in the second block [28]. This procedure was adopted to minimize the novelty effects of distractors while evaluating the effects of Aβ and age on performance under challenging conditions.…”

“…Each session was analyzed in terms of the relative number of hits (h = hits/hits+misses) for each signal length, and relative number of correct rejections (cr = correct rejections/correct rejections + false alarms). The overall measure of attentional performance was calculated as performance score (SAT/dSAT score) using the formula: (h – fa)/[2(h + fa) – (h + fa) 2 ] as described previously [25,28]. SAT/dSAT scores vary from +1.0 to −1.0; a score of +1.0 indicated that all responses on signal and non-signal trials were correct, 0 indicated the inability to discern signal from non-signal events, and −1.0 indicated that all responses were misses and false alarms.…”

“…Fifty cells were analyzed from three sections per animal. Prefrontal ChAT density was analyzed from cortical layers III/V using a grid counting procedure [25, 26, 28]. The threshold level of images was adjusted to maximize visualization of ChAT-immunopositive fibers using a macro created in Adobe Photoshop CS4.…”

Developmental suppression of forebrain trkA receptors and attentional capacities in aging rats: A longitudinal study

“…In another follow-up study, we observed that cholinergic-attentional capacities were partially rescued by blocking proNGF, a precursor of NGF, in trkA-suppressed aged rats (Yegla & Parikh, 2013). ProNGF is known to induce apoptotic signaling via its interaction with high-affinity p75 receptors and the sortilin complex (Nykjaer et al, 2004), and numerous studies indicated that the expression of this pro-neurotrophin is elevated in aging and AD (Al-Shawi et al, 2007; Al-Shawi et al, 2008; Fahnestock, Michalski, Xu, & Coughlin, 2001; Peng, Wuu, Mufson, & Fahnestock, 2004).…”