Accumulating evidence suggests that modulating the sigma 2 receptor (Sig2R) can provide beneficial effects for neurodegenerative diseases. Herein, we report the identification of a novel class of Sig2R ligands and their cellular andin vivoactivity in experimental models of Alzheimer's disease (AD). We report thatSAS‐0132 andDKR‐1051, selective ligands of Sig2R, modulate intracellular Ca²⁺levels in humanSK‐N‐SHneuroblastoma cells. The Sig2R ligandsSAS‐0132 andJVW‐1009 are neuroprotective in aC. elegansmodel of amyloid precursor protein‐mediated neurodegeneration. Since this neuroprotective effect is replicated by genetic knockdown and knockout ofvem‐1, the ortholog of progesterone receptor membrane component‐1 (PGRMC1), these results suggest that Sig2R ligands modulate aPGRMC1‐related pathway. Last, we demonstrate thatSAS‐0132 improves cognitive performance both in the Thy‐1hAPP^Lond/Swe+transgenic mouse model ofADand in healthy wild‐type mice. These results demonstrate that Sig2R is a promising therapeutic target for neurocognitive disorders includingAD. image

Alzheimer’s disease (AD), the most common form of dementia, is an age‐dependent progressive neurodegenerative disorder. β‐amyloid, a metabolic product of the amyloid precursor protein (APP), plays an important role in the pathogenesis of AD. The Thy1‐hAPP^Lond/Swe+ (line 41) transgenic mouse overexpresses human APP751 and contains the London (V717I) and Swedish (K670M/N671L) mutations. Here, we used a battery of behavioral tests to evaluate general activity, cognition, and social behavior in six‐month‐old male Thy1‐hAPP^Lond/Swe+ mice. We found hyperactivity in a novel environment as well as significant deficits in spontaneous alternation behavior. In fear conditioning (FC), Thy1‐hAPP^Lond/Swe+ mice did not display deficits in acquisition or in memory retrieval in novel context of tone‐cued FC, but they showed significant memory retrieval impairment during contextual testing in an identical environment. Surprisingly, in a standard hidden platform water maze, no significant deficit was detected in mutant mice. However, a delayed‐matching‐to‐place paradigm revealed a significant deficit in Thy1‐hAPP^Lond/Swe+ mice. Lastly, in the social novelty session of a three‐chamber test, Thy1‐hAPP^Lond/Swe+ mice exhibited a significantly decreased interest in a novel versus a familiar stranger compared to control mice. This could possibly be explained by decreased social memory or discrimination and may parallel disturbances in social functioning in human AD patients. In conclusion, the Thy1‐hAPP^Lond/Swe+ mouse model of AD displayed a behavioral phenotype that resembles, in part, the cognitive and psychiatric symptoms experienced in AD patients.

There is an urgent need for therapeutic approaches that can prevent or limit neuroinflammatory processes and prevent neuronal degeneration. Photobiomodulation (PBM), the therapeutic use of specific wavelengths of light, is a safe approach shown to have anti-inflammatory effects. The current study was aimed at evaluating the effects of PBM on LPS-induced peripheral and central inflammation in mice to assess its potential as an anti-inflammatory treatment. Daily, 30-min treatment of mice with red/NIR light (RL) or RL with a 40 Hz gamma frequency flicker for 10 days prior to LPS challenge showed anti-inflammatory effects in the brain and systemically. PBM downregulated LPS induction of key proinflammatory cytokines associated with inflammasome activation, IL-1β and IL-18, and upregulated the anti-inflammatory cytokine, IL-10. RL provided robust anti-inflammatory effects, and the addition of gamma flicker potentiated these effects. Overall, these results demonstrate the potential of PBM as an anti-inflammatory treatment that acts through cytokine expression modulation.

Emerging evidence suggests that endoplasmic reticulum (ER) stress may be involved in the pathogenesis of Alzheimer’s disease (AD). Recently, pharmacological modulation of the eukaryotic translation initiation factor-2 (eIF2α) pathway was achieved using an integrated stress response inhibitor (ISRIB). While members of this signaling cascade have been suggested as potential therapeutic targets for neurodegeneration, the biological significance of this pathway has not been comprehensively assessed in animal models of AD. The present study investigated the ER stress pathway and its long-term modulation utilizingin vitroandin vivoexperimental models of tauopathy (MAPT P301S)PS19 and amyloidosis (APP^Swe). We report that thapsigargin induces activating transcription factor-4 (ATF4) in primary cortical neurons (PCNs) derived from rat and APP^Swenontransgenic (nTg) and transgenic (Tg) mice. ISRIB mitigated the induction of ATF4 in PCNs generated from wild-type (WT) but not APP^Swemice despite partially restoring thapsigargin-induced translational repression in nTg PCNs.In vivo, C57BL/6J and PS19 mice received prolonged, once-daily administration of ISRIB. While the compound was well tolerated by PS19 and C57BL/6J mice, APP^Swemice treated per this schedule displayed significant mortality. Thus, the dose was reduced and administered only on behavioral test days. ISRIB did not improve learning and memory function in APP^SweTg mice. While ISRIB did not reduce tau-related neuropathology in PS19 Tg mice, no evidence of ER stress-related dysfunction was observed in either of these Tg models. Taken together, the significance of ER stress and the relevance of these models to the etiology of AD require further investigation.

Ischemic stroke is a leading cause of death and disability worldwide. Potential therapeutics aimed at neural repair and functional recovery are limited in their blood-brain barrier permeability and may exert systemic or off-target effects. We examined the effects of brain-derived neurotrophic factor (BDNF), delivered via an extended release HyStem^®-C hydrogel implant or vehicle, on sensorimotor function, infarct volume, and neuroinflammation, following permanent distal middle cerebral artery occlusion (dMCAo) in rats. Eight days following dMCAo or sham surgery, treatments were implanted directly into the infarction site. Rats received either vehicle, BDNF-only (0.167 µg/µL), hydrogel-only, hydrogel impregnated with 0.057 µg/µL of BDNF (hydrogel + BDNF_LOW), or hydrogel impregnated with 0.167 µg/µL of BDNF (hydrogel + BDNF_HIGH). The adhesive removal test (ART) and 28-point Neuroscore (28-PN) were used to evaluate sensorimotor function up to two months post-ischemia. The hydrogel + BDNF_HIGH group showed significant improvements on the ART six to eight weeks following treatment and their behavioral performance was consistently greater on the 28-PN. Infarct volume was reduced in rats treated with hydrogel + BDNF_HIGH as were levels of microglial, phagocyte, and astrocyte marker immunoexpression in the corpus striatum. These data suggest that targeted intracerebral delivery of BDNF using hydrogels may mitigate ischemic brain injury and restore functional deficits by reducing neuroinflammation.

Locus coeruleus (LC) noradrenergic (NE) neurons supply the main adrenergic input to the forebrain. NE is a dual modulator of cognition and neuroinflammation. NE neurons of the LC are particularly vulnerable to degeneration both with normal aging and in neurodegenerative disorders. Consequences of this vulnerability can be observed in both cognitive impairment and dysregulation of neuroinflammation. LC NE neurons are pacemaker neurons that are active during waking and arousal and are responsive to stressors in the environment. Chronic overactivation is thought to be a major contributor to the vulnerability of these neurons. Here we review what is known about the mechanisms underlying this neuronal vulnerability and combinations of environmental and genetic factors that contribute to confer risk to these important brainstem neuromodulatory and immunomodulatory neurons. Finally, we discuss proposed and potential interventions that may reduce the overall risk for LC NE neuronal degeneration.