Cannabidiol (CBD) has gained a lot of interest in recent years for its purported medicinal properties. CBD has been investigated for the treatment of anxiety, depression, epilepsy, neuroinflammation, and pain. Recently there has been an interest in CBD as a possible treatment for age-related disorders such as Alzheimer's disease and related disorders (ADRD). Here we tested the hypothesis that chronic CBD administration would improve learning and memory in the SAMP8 mouse model of Alzheimer's disease. SAMP8 mice aged 11 months (at the start of the study) were administered vehicle or CBD (3 or 30 mg/Kg) daily via oral gavage for 2 months. Vehicle-treated young SAMP8 mice (age 3 months at the start of the study) served as unimpaired controls. After 30 days of treatment (4 and 12 months of age), learning and memory, activity, anxiety, strength and dexterity were assessed. High dose CBD treatment significantly improved learning and memory of the 12-month-old mice in the T maze. Novel object recognition memory was also improved by CBD in aged CBD treated mice. Aged CBD treated mice also displayed less anxiety in the elevated plus maze test compared to controls. However, activity and strength levels were similar between groups. Biochemical analysis revealed decreased markers of oxidative stress, providing a possible mechanism by which CBD treatment impacts learning, memory, and anxiety. These results highlight the potential use of CBD as a therapeutic for age related cognitive impairment and dementia.

Sigma-1 (S1R) and sigma-2 (S2R) receptors are promising targets for treating Alzheimer disease (AD), playing important roles in cognitive function, with potential to mitigate neuropathology. The dual S1R/S2R receptor modulator (+/-)-cis-1-n-Butyl-8-methoxy-1,2,3a,4,5,9b-hexahydrobenz[e]indole hydrochloride (BBZI) was evaluated in the senescence-accelerated mouse prone 8 model of cognitive decline and AD as to behavior and hippocampal expression effects. Chronic BBZI treatment (0, 0.001, 0.01, 0.1, 1.0, or 10 mg/kg, i.p. daily, 27-days) was evaluated using a behavioral battery including open field activity (day-15), elevated plus maze (day-16), Y-maze (day-22), T-maze foot-shock avoidance (days 20 and 27), and novel object recognition (days 23 and 24). No changes were observed in open field, elevated plus maze, Y-maze, or novel object recognition tests at any dose of BBZI as compared with vehicle. BBZI enhanced T-maze foot-shock memory retention at 0.1 (P < .05, Bonferroni) and 1.0 mg/kg (P < .001, Bonferroni) compared with vehicle (day-27). In a separate cohort, a single-injection of BBZI (0, 0.001, 0.01, 0.1 & 1.0 μg, i.c.v.) with testing 7-days later showed a significant effect in the T-maze foot-shock test (P = .011) and enhanced memory retention behavior at 0.01 μg compared with vehicle (P < .05, Bonferroni). Poly(A) RNA sequencing evaluation of hippocampal tissue 24-hours after intracerebroventricular administered BBZI (1.0 μg/μL) versus vehicle showed unique gene expression changes, with notable effects relevant to mitochondrial energetics and synaptic function. Gene enrichment analysis identified affiliations with pathways involved in neurodegenerative disease. This data supports dual S1R/S2R receptor modulation as a promising strategy for AD treatment and identifies potential gene pathways involved. SIGNIFICANCE STATEMENT: Dual sigma receptor 1 and 2 modulator BBZI improved memory behavior in senescence-accelerated mouse prone 8 mice. Evaluation of senescence-accelerated mouse prone 8 hippocampal tissue 24 hours after BBZI (1.0 μg/μL i.c.v.) versus vehicle administration identified gene changes related to mitochondrial energetics and synaptic function. BBZI to mitigates cognitive decline behavior, impacting hippocampal genes critical for brain function.

Heterozygous loss-of-function mutations in the progranulin gene (GRN) are a major cause of frontotemporal dementia due to progranulin haploinsufficiency; complete deficiency of progranulin causes neuronal ceroid lipofuscinosis. Several progranulin-deficient mouse models have been generated, including both knockout mice and knockin mice harboring a common patient mutation (R493X). However, the GrnR493X mouse model has not been characterized completely. Additionally, while homozygous GrnR493X and Grn knockout mice have been extensively studied, data from heterozygous mice is still limited. Here, we performed more in-depth characterization of heterozygous and homozygous GrnR493X knockin mice, which includes biochemical assessments, behavioral studies, and analysis of fluid biomarkers. In the brains of homozygous GrnR493X mice, we found increased phosphorylated TDP-43 along with increased expression of lysosomal genes, markers of microgliosis and astrogliosis, pro-inflammatory cytokines, and complement factors. Heterozygous GrnR493X mice did not have increased TDP-43 phosphorylation but did exhibit limited increases in lysosomal and inflammatory gene expression. Behavioral studies found social and emotional deficits in GrnR493X mice that mirror those observed in Grn knockout mouse models, as well as impairment in memory and executive function. Overall, the GrnR493X knockin mouse model closely phenocopies Grn knockout models. Lastly, in contrast to homozygous knockin mice, heterozygous GrnR493X mice do not have elevated levels of fluid biomarkers previously identified in humans, including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in both plasma and CSF. These results may help to inform pre-clinical studies that use this Grn knockin mouse model and other Grn knockout models.

ID 20618 Poster Board 400 Paclitaxel, standard-of-care first-line chemotherapy for epithelial ovarian cancer and triple negative breast cancer, was shown to impair learning and memory functions in >50% of cancer survivors. Underpinning mechanisms of this major neurotoxicity are still mostly unknown, and there are no FDA-approved interventions. We developed a mouse model of paclitaxel-induced cognitive impairment whose cumulative dose is comparable to the total dose per cycle used in breast cancer patients. Paclitaxel-treated mice showed significant cognitive impairment in different hippocampal tests (T-maze, Novel Object Place Recognition test, NOPRT). Learning and memory functions were improved by co-administration of the selective A3 adenosine receptor (A3AR) agonist, MRS5980, without adversely affecting anxiety-like behavior and locomotor activity. Noteworthy, A3AR agonists possess anticancer activity and enhance the antitumor effects of paclitaxel. Moreover, we previously shown that targeting A3AR successfully improved neurocognitive functions after cisplatin, another widely used chemotherapeutic. Our previous studies in chemotherapy-induced peripheral neuropathy showed that Paclitaxel treatment caused a strong neuroinflammation in the central nervous system through the dysregulation of adenosine signaling. Adenosine kinase (ADK) is a key regulator of the adenosine signaling at its receptors. Here we demonstrated that the ADK inhibitor, ABT-702, attenuated paclitaxel-induced cognitive dysfunctions in mice. Mechanistically, these data suggest that paclitaxel-induced ADK dysregulation leads to a reduction of adenosine signaling at the A3AR and it is functionally linked to the development of cognitive dysfunctions. Collectively, the A3AR is emerging as an exciting novel approach in the treatment of a major chemotherapy-induced neurotoxicity. Keywords: Chemotherapy-induced cognitive impairment; A3 Adenosine receptor (A3AR); hippocampus; Paclitaxel; MRS5980. Fundings: This study was funded by the National Institutes of Health Grant RO1CA230512 (NIH) to Daniela Salvemini. Daniela Salvemini is a co-founder of BioIntervene Inc. All other authors claim no conflicts of interest.

The geroscience hypothesis states that a therapy that prevents the underlying aging process should prevent multiple aging related diseases. The mTOR (mechanistic target of rapamycin)/insulin and NAD+ (nicotinamide adenine dinucleotide) pathways are two of the most validated aging pathways. Yet, it's largely unclear how they might talk to each other in aging. In genome-wide CRISPRa screening with a novel class of N-O-Methyl-propanamide-containing compounds we named BIOIO-1001, we identified lipid metabolism centering on SIRT3 as a point of intersection of the mTOR/insulin and NAD+ pathways. In vivo testing indicated that BIOIO-1001 reduced high fat, high sugar diet-induced metabolic derangements, inflammation, and fibrosis, each being characteristic of non-alcoholic steatohepatitis (NASH). An unbiased screen of patient datasets suggested a potential link between the anti-inflammatory and anti-fibrotic effects of BIOIO-1001 in NASH models to those in amyotrophic lateral sclerosis (ALS). Directed experiments subsequently determined that BIOIO-1001 was protective in both sporadic and familial ALS models. Both NASH and ALS have no treatments and suffer from a lack of convenient biomarkers to monitor therapeutic efficacy. A potential strength in considering BIOIO-1001 as a therapy is that the blood biomarker that it modulates, namely plasma triglycerides, can be conveniently used to screen patients for responders. More conceptually, to our knowledge BIOIO-1001 is a first therapy that fits the geroscience hypothesis by acting on multiple core aging pathways and that can alleviate multiple conditions after they have set in.

ID 24673 Poster Board 167 Heterozygous GRN mutations cause frontotemporal dementia (FTD) due to haploinsufficiency of progranulin. The microRNA, miR-29b, negatively regulates progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested if ASOs can increase progranulin levels by sterically blocking the miR-29b binding site in the 39 UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein levels in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin levels in iPSC-derived neurons and in a humanized GRN mouse model. While the ASOs did not increase GRN mRNA levels, polysome profiling experiments revealed that the ASOs increase progranulin translation. Consistent with this, ASO treatment increased levels of newly synthesized progranulin protein. In FRET-based assays, the ASOs effectively competed miR-29b from binding to the GRN 39 UTR RNA. Together, these studies establish the mechanism of action is that these ASOs displace miR-29b from its binding site and thereby de-repress translation, resulting in increased synthesis of progranulin protein. Our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites; this ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.

A common cause of frontotemporal dementia (FTD) are nonsense mutations in the progranulin (GRN) gene. Because nonsense mutations activate the nonsense-mediated RNA decay (NMD) pathway, we sought to inhibit this RNA turnover pathway as a means to increase progranulin levels. Using a knock-in mouse model harboring a common patient mutation, we tested whether either pharmacological or genetic inhibition of NMD upregulates progranulin in these GrnR493X mice. We first examined antisense oligonucleotides (ASOs) targeting an exonic region in GrnR493X mRNA predicted to block its degradation by NMD. As we previously reported, these ASOs effectively increased GrnR493X mRNA levels in fibroblasts in vitro. However, following CNS delivery, we found that none of the 8 ASOs we tested increased Grn mRNA levels in the brains of GrnR493X mice. This result was obtained despite broad ASO distribution in the brain. An ASO targeting a different mRNA was effective when administered in parallel to wild-type mice. As an independent approach to inhibit NMD, we examined the effect of loss of an NMD factor not required for embryonic viability: UPF3b. We found that while Upf3b deletion effectively perturbed NMD, it did not increase Grn mRNA levels in Grn+/R493X mouse brains. Together, our results suggest that the NMD-inhibition approaches that we used are likely not viable for increasing progranulin levels in individuals with FTD caused by nonsense GRN mutations. Thus, alternative approaches should be pursued.

Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3' UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose -dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET -based assays, the ASOs effectively competed for miR-29b from binding to the GRN 3' UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by polysome profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.

ID 53923 Poster Board 137 Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairments and brain amyloid-beta (Aβ) aggregation. Neprilysin (NEP) is a primary Aβ-degrading enzyme, activated by the neuropeptide somatostatin (ssT) through a receptor mediated action (Saito et al., 2005, Nat Med 11(4):434-439). Of the five ssT receptors, the subtype-4 (ssTR4) shows the greatest promise for AD treatment targeting. ssTR4 has optimal brain localization, being highly expressed in neurons of the neocortex, and hippocampus (Viollet et al., 2008, Mol Cell Endocrinol 286(1-2):75-87). We previously showed ssTR4 agonist actions increase spatial and recognition memory in Senescence Accelerated Mouse-Prone 8 (SAMP8) and APPswe mouse models of AD, with capacity to reduce Aβ-oligomer protein expression (Sandoval et al., 2012 Eur J Pharmacol 683(1-3):116-124; Sandoval et al., 2013, Brain Res 1520:145-56). Herein, we evaluated the novel ssTR4 agonist SM-I-26 on memory behavior and NEP activity in SAMP8 mice. SM-I-26 has high ssTR4 affinity (Ki=12 nM), selectivity (>400-fold selective over other ssTR subtypes), and activity (EC50=17 nM). Male 12-month-old SAMP8 mice were administered 0.01, 0.1, or 1.0 μg (i.c.v.) of SM-I-26 or vehicle for memory retention testing using the T-maze foot-shock avoidance test (memory retention 1-week post-injection, n = 7-8/group). NEP activity was tested at 1.0 μg (i.c.v.) against vehicle control in cortical and hippocampal tissue 24-h post injection (n = 7/group). SM-I-26 improved behavioral retention of the T-maze shock avoidance task in a dose-responsive manner (P<0.0001, one-way ANOVA), with 0.1 and 1.0 μg SM-I-26 significantly reducing the mean trials to criterion when compared to vehicle (P<0.0001, Dunnet’s T3). Within cortical tissue, SM-I-26 increased NEP activity (P < 0.05, independent t-test) compared to vehicle controls. A similar but non-significant trend between SM-I-26 and NEP activity was observed in hippocampal tissue. Data shows i.c.v. administration of the ssTR4 agonist SM-I-26 improves memory behavior in SAMP8 mice and increases NEP activity in primary tissues associated with AD impairments. The potential of a ssTR4 agonist therapeutic for AD treatment is supported by this work. This work has been supported by the National Institutes of Health, National Institute on Aging, R01AG047858.

GRN mutations cause frontotemporal dementia (FTD) due to haploinsufficiency of progranulin. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but ASO-based strategies for increasing target protein levels are limited. Here, we tested if ASOs can increase progranulin levels by sterically blocking the miR-29b binding site in the 3’ UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein levels in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin levels in iPSC-derived neurons and in a humanized GRN mouse model. Ribosomal profiling experiments revealed that the ASOs increase the rate of progranulin translation. Consistent with this, ASO treatment increased levels of newly synthesized progranulin protein. In FRET-based assays, the ASOs effectively competed miR29b from binding to the GRN 3’ UTR RNA. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.

GRN mutations cause frontotemporal dementia (FTD) due to haploinsufficiency of progranulin. Several microRNAs (miRs), including miR-29b, have been reported to negatively regulate progranulin protein levels. Here, we tested if antisense oligonucleotides (ASOs) – which are versatile modulators of target mRNA/protein levels – can be used to increase progranulin levels by sterically blocking the miR-29b binding site. We designed 48 ASOs targeting the miR-29b binding site in the 3’ UTR of the human GRN mRNA. We treated H4 neuroglioma cells and iPSC-derived neurons with these ASOs and subsequently measured progranulin protein levels by western blot and ELISA. We performed further studies to determine the mechanism of action of these ASOs using ribosomal profiling, metabolic labeling, and FRET assays. We identified 16 ASOs that increased progranulin protein levels in a dose-dependent manner. Ribosomal profiling experiments revealed that cells treated with ASOs had marked enrichment in GRN mRNA in heavy polyribosome fractions, compared to cells treated with a scrambled control ASO, suggesting that the ASOs increase the rate of progranulin translation. Consistent with this, ASO treatment resulted in increased levels of newly synthesized progranulin protein. FRET-based assays showed that ASOs can effectively compete miR-29b from its binding site in the GRN 3’ UTR RNA under in vitro conditions. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.

Cancer-related cognitive impairment (CRCI) is a major neurotoxicity affecting more than 50% of cancer survivors. The underpinning mechanisms are mostly unknown, and there are no FDA-approved interventions. Sphingolipidomic analysis of mouse prefrontal cortex and hippocampus, key sites of cognitive function, revealed that cisplatin increased levels of the potent signaling molecule sphingosine-1-phosphate (S1P) and led to cognitive impairment. At the biochemical level, S1P induced mitochondrial dysfunction, activation of NOD-, LRR-, and pyrin domain–containing protein 3 inflammasomes, and increased IL-1β formation. These events were attenuated by systemic administration of the functional S1P receptor 1 (S1PR1) antagonist FTY720, which also attenuated cognitive impairment without adversely affecting locomotor activity. Similar attenuation was observed with ozanimod, another FDA-approved functional S1PR1 antagonist. Mice with astrocyte-specific deletion of S1pr1 lost their ability to respond to FTY720, implicating involvement of astrocytic S1PR1. Remarkably, our pharmacological and genetic approaches, coupled with computational modeling studies, revealed that cisplatin increased S1P production by activating TLR4. Collectively, our results identify the molecular mechanisms engaged by the S1P/S1PR1 axis in CRCI and establish S1PR1 antagonism as an approach to target CRCI with therapeutics that have fast-track clinical application.

The neural functions of adropin, a secreted peptide highly expressed in the brain, have not been investigated. In humans, adropin is highly expressed in astrocytes and peaks during critical postnatal periods of brain development. Gene enrichment analysis of transcripts correlating with adropin expression suggests processes relevant to aging-related neurodegenerative diseases that vary with age and dementia state, possibly indicating survivor bias. In people aged <40 y and ‘old-old’ (>75 y) diagnosed with dementia, adropin correlates positively with genes involved in mitochondrial processes. In the ‘old-old’ without dementia adropin expression correlates positively with morphogenesis and synapse function. Potent neurotrophic responses in primary cultured neurons are consistent with adropin supporting the development and function of neural networks. Adropin expression in the ‘old-old’ also correlates positively with protein markers of tau-related neuropathologies and inflammation, particularly in those without dementia. How variation in brain adropin expression affects neurological aging was investigated using old (18-month) C57BL/6J mice. In mice adropin is expressed in neurons, oligodendrocyte progenitor cells, oligodendrocytes, and microglia and shows correlative relationships with groups of genes involved in neurodegeneration and cellular metabolism. Increasing adropin expression using transgenesis improved spatial learning and memory, novel object recognition, resilience to exposure to new environments, and reduced mRNA markers of inflammation in old mice. Treatment with synthetic adropin peptide also reversed age-related declines in cognitive functions and affected expression of genes involved in morphogenesis and cellular metabolism. Collectively, these results establish a link between adropin expression and neural energy metabolism and indicate a potential therapy against neurological aging.

Obesity-related metabolic dysregulation causes mild cognitive impairment and increased risk for dementia. We used an LDLR-deficient C57BL/6J mouse model (LDLRKO) to investigate whether adropin, a neuropeptide linked to neurodegenerative diseases, improves cognitive function in situations of metabolic dysregulation. Adropin transgenic mice (AdrTG) were crossed with LDLRKO; male and female progeny were fed a high fat diet for 3-months. Male chow-fed wild type (WT) mice were used as controls. Diet-induced obesity and LDLR-deficiency caused severe dyslipidemia, irrespective of sex. The AdrTG prevented reduced adropin protein levels in LDLRKO cortex. In males, metabolic dysregulation and AdrTG genotype significantly and bi-directionally affected performance in the novel object recognition (NOR) test, a declarative hippocampal memory task (discrimination index mean ± SE for WT, 0.02 ± 0.088; LDLRKO, -0.115 ± 0.077; AdrTG;LDLRKO, 0.265 ± 0.078; genotype effect, p = 0.009; LDLRKO vs. AdrTG;LDLRKO, P < 0.05). A 2-way ANOVA (fixed variables: sex, AdrTG genotype) indicated a highly significant effect of AdrTG (P = 0.003). The impact of the diet-genotype interaction on the male mouse brain was investigated using RNA-seq. Gene-ontology analysis of transcripts showing fold-changes of>1.3 or <-1.3 (P < 0.05) indicated metabolic dysregulation affected gene networks involved in intercellular/neuronal signaling, immune processes, angiogenesis, and extracellular matrix organization. The AdrTG selectively attenuated the impact of metabolic dysregulation on intercellular/neuronal signaling pathways. Intercellular/neuronal signaling pathways were also the predominant processes overrepresented when directly comparing AdrTG;LDLRKO with LDRKO. In summary, adropin overexpression improves cognitive function in severe metabolic dysregulation through pathways related to cell-cell communication and neuronal processes, and independently of preventing inflammatory responses.

Abstract Adropin is most abundant in neural tissues yet its neurological functions are unclear. Data from post-mortem human brain tissue samples indicates adropin expression occurs predominantly in astrocytes, peaks during critical post-natal periods of brain development, and then declines with aging. Previous experiments indicate adropin regulates mitochondrial metabolism. Gene clusters correlating with adropin are age- and dementia-specific, possibly indicating survivor bias. In people aged <40y adropin correlates positively with genes involved in mitochondrial metabolism, APOE and Clusterin. In the ‘old-old’ (>75y) with dementia, adropin expression correlates with genes linked to mitochondrial metabolism and neurodegenerative conditions. In the ‘old-old’ (>75y) without dementia, adropin correlates with genes involved in morphogenesis, growth of neuronal processes (dendrites, axons) and synapse function. Accordingly, adropin elicits neurotrophic responses in primary cultured neurons. Adropin expression also correlates positively with protein markers of tau-related neuropathologies and inflammation, particularly in people without dementia, indicating a link to cellular stressors. How variation in brain adropin expression affects neurological aging was investigated using C57BL/6J mice. In mice, adropin is more widely expressed in neurons, oligodendrocyte progenitor cells, oligodendrocytes, and microglia. Preventing the decline in expression observed with aging of mice using transgenesis improved cognitive function and resilience, while also reducing mRNA markers of inflammation in 18-month old mice. Treating 18-month old mice with adropin peptide also improved cognitive performance. These results link adropin expression to cellular energy metabolism and stress responses in the brain and indicates a possible relationship with aging-related cognitive decline.

Somatostatin receptor-4 (SST4) is highly expressed in brain regions affiliated with learning and memory. SST4 agonist treatment may act to mitigate Alzheimer's disease (AD) pathology. An integrated approach to SST4 agonist lead optimization is presented herein. High affinity and selective agonists with biological efficacy were identified through iterative cycles of a structure-based design strategy encompassing computational methods, chemistry, and preclinical pharmacology. 1,2,4-Triazole derivatives of our previously reported hit (4) showed enhanced SST4 binding affinity, activity, and selectivity. Thirty-five compounds showed low nanomolar range SST4 binding affinity, 12 having a Ki < 1 nM. These compounds showed >500-fold affinity for SST4 as compared to SST2A. SST4 activities were consistent with the respective SST4 binding affinities (EC50 < 10 nM for 34 compounds). Compound 208 (SST4Ki = 0.7 nM; EC50 = 2.5 nM; >600-fold selectivity over SST2A) display a favorable physiochemical profile, and was advanced to learning and memory behavior evaluations in the senescence accelerated mouse-prone 8 model of AD-related cognitive decline. Chronic administration enhanced learning with i.p. dosing (1 mg kg-1) compared to vehicle. Chronic administration enhanced memory with both i.p. (0.01, 0.1, 1 mg kg-1) and oral (0.01, 10 mg kg-1) dosing compared to vehicle. This study identified a novel series of SST4 agonists with high affinity, selectivity, and biological activity that may be useful in the treatment of AD.

Adropin is most abundant in neural tissues yet its neurological functions are unclear. Data from post-mortem human brain tissue samples indicates adropin expression occurs predominantly in astrocytes, peaks during critical post-natal periods of brain development, and then declines with aging. Previous experiments indicate adropin regulates mitochondrial metabolism. Gene clusters correlating with adropin are age- and dementia-specific, possibly indicating survivor bias. In people aged <40y adropin correlates positively with genes involved in mitochondrial metabolism, APOE and Clusterin. In the ‘old-old’ (>75y) with dementia, adropin expression correlates with genes linked to mitochondrial metabolism and neurodegenerative conditions. In the ‘old-old’ (>75y) without dementia, adropin correlates with genes involved in morphogenesis, growth of neuronal processes (dendrites, axons) and synapse function. Accordingly, adropin elicits neurotrophic responses in primary cultured neurons. Adropin expression also correlates positively with protein markers of tau-related neuropathologies and inflammation, particularly in people without dementia, indicating a link to cellular stressors. How variation in brain adropin expression affects neurological aging was investigated using C57BL/6J mice. In mice, adropin is more widely expressed in neurons, oligodendrocyte progenitor cells, oligodendrocytes, and microglia. Preventing the decline in expression observed with aging of mice using transgenesis improved cognitive function and resilience, while also reducing mRNA markers of inflammation in 18-month old mice. Treating 18-month old mice with adropin peptide also improved cognitive performance. These results link adropin expression to cellular energy metabolism and stress responses in the brain and indicates a possible relationship with aging-related cognitive decline.

Progranulin is a lysosomal and secreted protein that has neurotrophic properties and promotes neurite outgrowth in vitro. Mutations in the progranulin gene have been found to cause frontotemporal dementia. Additionally, reduced progranulin levels may be a risk factor for the development of Alzheimer's disease (AD). Studies in mouse models of AD support this notion: reducing progranulin exacerbates disease progression whereas increasing progranulin confers protection. However, the physiologic function of progranulin in the CNS is not known. We tested the effects of CNS-administered progranulin in the cognition in young male CD-1 mice, (3-months of age), old C57/BL male mice (24 months of age), 3xTG-AD male and female mice (13 months of age) and SAMP8 mice (12 months of age). Immediately following T maze foot shock avoidance training, CD-1 mice (n = 10 per group) were injected intracerebroventricularly (ICV) with progranulin (0, 0.005, 0.1 or 1.0 ug/2 ul). C57/BL 24 month old (n= 8~9/group) and the 13 month old 3xTG-AD mice (n = 8~9/group), were given either 0 or 1.0 ug/2 ul immediately after training. The 12 month old SAMP8 mice (n = 10~11/group) were given 0, 0.1 or 1.0 ug/2ul. Retention was assessed one week after training. The number of trails to reach a criterion of 5 avoidances in 6 consecutive trails was determined. Following behavioral testing, cortex, hippocampus, and plasma were harvested. CD-1 mice that received and an ICV injection of progranulin 0.1 and 1.0 ug/2 ul had significantly improved retention in T-maze than the mice which receive vehicle. These mice took significantly fewer trials to make an avoidance than the mice which received 0 ug/2 ul. Progranulin at 1.0 ug/2 ul improved retention in the 24 month old C57/BL mice, the 13 month old 3xTG-AD mice Progranulin at 0.1 and 1.0 ug/2ul improve retention in the 12 month old SAMP8 mice. It is becoming increasingly apparent that progranulin is involved in memory dysfunction. We found that progranulin has a direct influence on memory consolidation as its administration following foot shock avoidance training leads to improved memory retention. Our studies suggest that progranulin can directly modulate memory in both cognitively normal and AD mice, indicating that is has an important role not only in the pathogenesis of frontotemporal dementia, but in normal aged-related cognitive decline and AD progression as well.

The use of cannabidiol (CBD) has grown rapidly over the last few years. CBD has been purported to work on a range of conditions, including anxiety, pain, and psychosis. There has been recent interest in CBD as a treatment for age-related cognitive disorders due to its antioxidant and anti-inflammatory properties. Here, we tested the effects of chronic CBD administration on learning and memory in the SAMP8 mouse model of Alzheimer’s disease. SAMP8 mice develop an age-related impairment in learning and memory which corresponds to an increase in amyloid-β (Aβ), hyperphosphorylated tau, oxidative stress, impaired efflux of Aβ across the blood-brain barrier and neuroinflammation. SAMP8 mice starting at 11 months of age were treated with CBD (0, 3 or 30 mg/kg) daily via oral administration for 60 days. A 3 month old SAMP8 group receiving vehicle served as an unimpaired control. After 30 days of treatment, learning and memory (T-maze and novel object recognition), activity in open field, anxiety in the elevated plus maze, and strength were assessed. At the end of behavioral testing brains were collected for analysis. Mice which received CBD 30 mg/kg had significant improvement in learning and memory in the T-maze, taking fewer trials to reach criterion than 12 month old vehicle treated mice. CBD improved novel object recognition memory of 12 month old SAMP8 mice, which spent significantly more time with the novel object in the 24-hour retention test than the age-matched vehicle treated controls. While there was no difference in total distance traveled measured by open field activity, the mice that that received CBD displayed decreased anxiety at both 3 and 30 mg/kg/day doses compared to the age-matched control. The mice that received 3 mg/kg/day had significantly less anxiety than the young control group. CBD had no significant effects on the measures of strength in the aged mice. Analysis of brain tissue indicate that CBD significantly decreased markers of oxidative stress. Our results indicate that CBD improves both spatial and recognition memory and decreases anxiety. The actions appear to be primarily through its antioxidant properties. CBD is a potential treatment for age-related dementia.