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Published in final edited form as: Neurosci Lett. 2023 Jan 16;797:137080. doi: 10.1016/j.neulet.2023.137080

BCI-838, an orally active mGluR2/3 receptor antagonist pro-drug, rescues learning behavior deficits in the PS19 MAPTP301S mouse model of tauopathy

Georgina Perez-Garcia a,b, Mesude Bicak c,d, Jean-Vianney Haure-Mirande a, Gissel M Perez b, Alena Otero-Pagan b, Miguel A Gama Sosa e,f, Rita De Gasperi b,e, Mary Sano b,e,g, Carrolee Barlow h,i, Fred H Gage h,j, Benjamin Readhead k, Michelle E Ehrlich a,c, Sam Gandy a,b,e,g,l,*, Gregory A Elder a,e,g,m,*
PMCID: PMC9974759  NIHMSID: NIHMS1866858  PMID: 36657633

Abstract

Tauopathies are a heterogeneous group of neurodegenerative disorders that are clinically and pathologically distinct from Alzheimer’s disease (AD) having tau inclusions in neurons and/or glia as their most prominent neuropathological feature. BCI-838 (MGS00210) is a group II metabotropic glutamate receptor (mGluR2/3) antagonist pro-drug. Previously, we reported that orally administered BCI-838 improved learning behavior and reduced anxiety in Dutch (APPE693Q) transgenic mice, a model of the pathological accumulation of Aβ oligomers found in AD. Herein, we investigated effects of BCI-838 on PS19 male mice that express the tauopathy mutation MAPTP301S associated with human frontotemporal lobar degeneration (FTLD). These mice develop an aging-related tauopathy without amyloid accumulation. Mice were divided into three experimental groups: (1) non-transgenic wild type mice treated with vehicle, (2) PS19 mice treated with vehicle and (3) PS19 mice treated with 5 mg/kg BCI-838. Groups of 10–13 mice were utilized. Vehicle or BCI-838 was administered by oral gavage for 4 weeks. Behavioral testing consisting of a novel object recognition task was conducted after drug administration. Two studies were performed beginning treatment of mice at 3 or 7 months of age. One month of BCI-838 treatment rescued deficits in recognition memory in PS19 mice whether treatment was begun at 3 or 7 months of age. These studies extend the potential utility of BCI-838 to neurodegenerative conditions that have tauopathy as their underlying basis. They also suggest an mGluR2/3 dependent mechanism as a basis for the behavioral deficits in PS19 mice.

Keywords: BCI-838, frontotemporal dementia, metabotropic glutamate receptors 2/3, microtubule associated protein tau (MAPT), tauopathy, transgenic mice

1. Introduction

The tauopathies constitute a heterogeneous group of diseases in which tau inclusions accumulate in neurons or glia [14, 19, 26, 30]. These disorders include Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). Genetic studies support the distinctiveness of these disorders with dominantly inherited familial cases of AD being associated with mutations in the amyloid precursor protein and the presenilins [2] while tauopathies have been associated with mutations in the microtubule associated protein tau (MAPT) [20] as well as several other genes, including C9orf72 and progranulin (GRN) [11]. C9orf72 is the most common genetic cause of FTLD [11]. However, more than 50 different MAPT mutations have been reported to cause FTLD [20], and the most widely used animal model of tauopathy is the PS19 MAPTP301S mouse [28].

Metabotropic glutamate receptors (mGluRs) regulate glutamatergic neurotransmission. BCI-838 (MGS0210) is a group II metabotropic glutamate receptor (mGluR2/3) antagonist pro-drug [18, 21]. Previously, we reported that orally administered BCI-838 improved learning behavior and reduced anxiety in Dutch (APPE693Q) transgenic (Tg) mice, a model of the pathological accumulation of Aβ oligomers found in AD [18]. In a separate study, we found that BCI-838 reversed post-traumatic stress disorder-related traits in a rat model of blast-induced traumatic brain injury [21].

Herein, we investigated effects of BCI-838 in PS19 mice [28]. These mice develop an aging-related tauopathy without amyloid accumulation [28]. Filamentous tangle-like tau deposits are present by 6 months of age, which progressively accumulate and are associated with atrophy and neuronal loss in the hippocampi as well as other brain regions by 9–12 months of age [28]. We show that BCI-838 rescues deficits in recognition memory in PS19 mice whether treatment is begun at 3 or 7 months of age. These studies extend the potential utility of BCI-838 to neurodegenerative conditions that have tauopathy as part of their underlying basis and implicate mGluR2/3 dependent mechanisms as a basis for the behavioral deficits in PS19 mice.

2. Materials and Methods

2.1. Animals

Experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the James J. Peters VA Medical Center (Bronx NY). Studies were conducted in compliance with US Public Health Service policy on the humane care and use of laboratory animals, the NIH Guide for the Care and Use of Laboratory Animals, and all applicable Federal regulations governing protection of animals in research. Male Prnp-MAPT*P301S(PS19Vle/J) transgenic mice were obtained from the Jackson Laboratories on the C57BL/6 x C3H background. Mice were backcrossed for 9 generations onto the C57BL6/J background and studied were conducted on that background. Non-transgenic male littermates were used as controls.

2.2. Drug administration

BCI-838 was dissolved in a solution of 5% carboxymethylcellulose (CMC; Sigma Aldrich) and 0.3% 2N hydrochloric acid solution (Sigma Aldrich) as previously described [18, 21]. BCI-838 administration was conducted daily for 4 weeks by personnel experienced in oral gavage of mice using a 5-cm straight stainless-steel gavage needle with a 2-mm ball tip (Fisher Scientific) [21]. Two cohorts were studied with drug administration beginning at either 3 months or 7 months of age.

2.3. Novel object recognition (NOR)

NOR testing began at the end of the 4 weeks of drug administration. Testing utilized groups of 10–13 mice. Mice were habituated to the circular arena (30 cm length × 30 cm width × 40 cm height) for a period of 10 min on the day (24 h) before training. On the training day, two identical objects were placed on opposite ends of the empty arena, and the mouse was allowed to freely explore the objects for 7 min. After 2 h, during which the mouse was held in its home cage, one of the two familiar objects (FOs) was replaced with a novel object (NO), and the mouse was allowed to freely explore the FO and NO for 5 min to assess short-term memory (STM). After 24 h, during which the mouse was held in its home cage, the NO from the STM testing was replaced with a NO different from the one used during STM testing but placed in the same location. The FO remained in the same location for all three sessions. The mouse was allowed to freely explore the FO and NO for 5 min to assess long-term memory (LTM). Object exploration was defined as sniffing or touching the object with the vibrissae or when the animal’s head was oriented toward the object with the nose placed at a distance of < 2 cm from the object. All sessions were recorded by video camera (Sentech) and analyzed with ANYMAZE software (San Diego Instruments). In addition, offline analysis by an investigator blind to the treatment status of the animals was performed. Objects to be discriminated were of different size, shape, and color, and were made of Lego plastic material. All objects were wiped with 70% ethanol between trials. Raw exploration times for each object were expressed in seconds. A discrimination index (DI) was calculated by subtracting the time spent exploring the familiar object (TF) from the time spent exploring the novel object (TN) and dividing by the total time spent exploring either object using the the formula: DI = (TN − TF)/(TN + TF).

2.4. Statistical analyses

Values are expressed as mean ± SEM. Statistical testing was performed using Prism 9.4.1 (GraphPad Prism) and SPSS v27.0.1.0 (IBM). When two group comparisons were made, means were compared using unpaired t-tests. If three groups were compared, a one-way ANOVA was calculated, and if the ANOVA was significant, post-hoc comparisons between groups were made using Fisher’s LSD.

3. Results

3.1. Experimental design for treatment of PS19 mice with BCI-838

The experimental design is shown in Fig. 1. Mice were divided into three experimental groups: (1) non-transgenic wild type mice treated with vehicle (non-Tg + veh), (2) PS19 mice treated with vehicle (PS19 + veh) and (3) PS19 mice treated with 5 mg/kg BCI-838 (PS19 + BCI-838). A dose of 5 mg/kg was chosen based on a prior study showing that this dose reversed impairments in learning and reduced anxiety in Dutch APP transgenic mice [18].

Fig. 1.

Fig. 1.

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Experimental design. Mice were divided into three experimental groups: (1) non-transgenic wild type mice treated with vehicle (non-Tg + veh), (2) PS19 MAPT transgenic mice treated with vehicle (PS19 + veh) and (3) PS19 mice treated with 5 mg/kg BCI-838 (PS19 + BCI-838).

In this design comparison of the single group of untreated non-Tg mice (Group 1) to untreated PS19 mice (Group 2) served as a positive control for appearance of the transgene-related behavioral phenotype while comparison of the treated group (Group 3) to group 2 measured effectiveness of BCI-838 treatment. Vehicle or BCI-838 was administered by oral gavage for 4 weeks. Two studies were performed beginning treatment at 3 or 7 months of age. Time points were chosen based on prior studies in the PS19 line [28] to represent one time point before tau pathology is present (3 months) and a time point when tau pathology is well established (7 months).

3.2. Body weight

Drug administration did not seem to affect general health of the animals. Weights of animals before and after drug administration are shown in Fig. 2. Pre-gavage, at both 3 months (Fig. 2A) and 7 months (Fig. 2B) of age PS19 mice weighed less their non-Tg counterparts with no differences in weight between the PS19 mice that were randomized to vehicle or BCI-838 treatment (data not shown). After one month of treatment, PS19 + veh still weighed less than non-Tg + veh. However, PS19 + BCI-838 did not differ significantly from non-Tg + veh. In mice treated beginning at 7 months of age (Fig. 2B), after one month of BCI-838 treatment, both PS19 + veh and PS19 +BCI-838 weighed less than non-Tg + veh. However, PS19 + BCI-838 weighed more than PS19 + veh. Collectively, these studies suggest that BCI-838 reduced weight loss in PS19 mice treated with vehicle.

Fig. 2.

Fig. 2.

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Weights of mice before and after treatment with BCI-838. Shown are weights pre and post gavage in mice in which treatment with vehicle or BCI-838 was begun at 3 months (A) or 7 months (B) of age. Groups pre-gavage were compared using unpaired t-tests (*p < 0.05, ****p < 0.0001). At 3 months, a one-way ANOVA post-gavage was significant (F 2, 33 = 4.789, p = 0.0149). Post-hoc tests (Fisher’s LSD) showed that PS19 + veh weighed significantly less than non-Tg + veh. At 7 months, a one-way ANOVA post-gavage was significant (F 2, 29 = 17.66, p < 0.001) with post-hoc tests showing that both PS19 + veh and PS19 + BCI-838 weighed less than non-Tg +veh while PS19 +BCI-838 weighed more than PS19 + veh. Asterisks in panels post-gavage indicate values significantly different between groups (*p < 0.05, **p < 0.01, ****p < 0.0001, Fisher’s LSD).

3.3. BCI-838 reversed recognition memory deficits in PS19 mice when treatment was begun at 3 months of age

Novel object recognition (NOR) is a standard behavioral test used to evaluate hippocampal- and perirhinal-dependent learning behavior; NOR is widely used to assess progression of learning deficits in mouse models of neurodegenerative diseases. As shown in Figure 3, during training in mice treated starting at 3 months of age, no differences in object preference were observed among groups (Fig. 3A). Two hours later (short term memory; STM)(Fig. 3B), when one of the familiar objects (FO) presented during training was replaced with a novel object (NO), non-Tg + veh mice spent more time exploring the NO than the FO (p = 0.0114) while PS19 + veh mice explored the FO and NO similar amounts of time (p = 0.6329), consistent with in this study recognition memory being impaired in PS19 mice treated with vehicle at four months of age. By contrast, PS19 mice treated for 4 weeks with BCI-838 spent more time exploring the NO than the FO (p = 0.0039). A discrimination index, which measures the relative tendency to explore the NO vs. FO further confirmed impairment of recognition memory in PS19 mice and its rescue by BCI-838 treatment (Fig. 3D).

Fig. 3.

Fig. 3.

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Novel object recognition (NOR) testing of mice that began BCI-838 treatment at 3 months of age. Non-transgenic mice (n = 13) treated with vehicle (non-Tg + veh), transgenic mice (n = 12) treated with vehicle (PS19 + veh) and transgenic mice (n = 13) treated with BCI-838 (PS19 + BCI-838) were tested. Panels (A)-(C) show time exploring the objects (OB1 and OB2) during the training session (A) as well as exploration of the previously presented familiar object (FO) compared to the novel object (NO) when presented 2 h (short-term memory, STM)(B) or 24 h (long-term memory, LTM)(C) later. NOR recognition was treated as a binary construct, namely that mice in each group either recognized the FO more than the NO in the STM and LTM testing or did not. Comparisons within each group were made using unpaired t-tests. Asterisks indicate significant differences (*p < 0.05, **p < 0.01, unpaired t-tests). Panels (D) and (E) show a discrimination index (DI) and panel (F) total time exploring objects during the sessions. One-way ANOVAs revealed significant effects for DI STM (D) (F 2, 32 = 10.60, p = 0.0003), DI LTM (E) (F 2, 32 = 3.858, p = 0.0316) and LTM exploration time (F)(F 2, 32 = 4.448, p = 0.0197). One-way ANOVAs for exploration time in training and STM sessions (F) were not significant. Asterisks in panels (D)-(F) indicate values significantly different between groups (*p < 0.05, **p < 0.01, ****p < 0.0001, Fisher’s LSD).

Long-term memory (LTM) was tested twenty-four hours later by replacing one of the now familiar objects with another NO (Fig. 3C). In LTM testing, a similar pattern of impairment was seen in PS19 mice with PS19 + veh mice exploring the NO no more than the FO. This impairment was not present in non-Tg + veh mice and was rescued in PS19 + BCI-838 mice (Fig. 3C and D). Recognition memory in LTM was also rescued as judged by a discrimination index (Fig. 3E). Total object exploration times did not differ between groups in training or STM testing, while in LTM testing, PS19 + veh explored the objects less than PS19 + BCI-838 (Fig. 3F).

3.4. BCI-838 improved recognition memory impairment in PS19 mice when treatment was begun at 7 months of age

Figure 4 shows NOR testing of mice treated with vehicle or BCI-838 starting at 7 months of age. No differences in object preference were noted during training (Fig. 4A). In both STM (Fig. 4B) and LTM (Fig. 4C) testing, non-Tg + veh mice spent more time exploring the NO than the FO (p = 0.0005 STM; p = 0.004 LTM) while PS19 + veh mice explored the FO and NO similar amounts of time (p = 0.6736 STM; p = 0.9044 LTM), consistent with in this study impaired recognition memory at 8 months of age in PS19 mice treated with vehicle. This effect was rescued in PS19 + BCI-838 mice which explored the NO more than the FO in both STM (p < 0.0001) and LTM (p = 0.0026) testing. When a discrimination index was calculated in both STM (Fig. 4D) and LTM (Fig. 4E) testing, non-Tg + veh mice exhibited higher discrimination index scores than PS19 + veh mice (p < 0.01); PS19 + BCI-838 mice exhibited higher discrimination index scores than PS19 + veh mice (p < 0.01), while PS19 + BCI-838 were not different from non-Tg + veh. PS19 + BCI-838 mice also spent more total time exploring the objects during all three testing sessions (Figs 4F-H).

Fig. 4.

Fig. 4.

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Novel object recognition (NOR) testing of mice that began BCI-838 treatment at 7 months of age. Non-transgenic mice (n = 13) treated with vehicle (non-Tg + veh), PS19 mice (n = 11) treated with vehicle (PS19 + veh) and PS19 mice (n = 11) treated with BCI-838 (PS19 + BCI-838) were tested in an NOR task. Panels (A)-(C) show time spent exploring the objects (OB1 and OB2) during the NOR training session (A) as well as exploration of the previously presented familiar object (FO) compared to the novel object (NO) when presented 2 h (short-term memory, STM)(B) or 24 h (long-term memory, LTM)(C) later. Statistical comparisons were made as described in Figure 3. Asterisks indicate significantly differences (* p < 0.05, ** p < 0.01, unpaired t-tests). Panels (D) and (E) show discrimination indices and panels (F)-(H) total time exploring the objects during the indicated sessions. One-way ANOVAs revealed significant effects for DI STM (D) (F 2, 32 = 6.939, p = 0.003), DI LTM (E) (F 2, 32 = 7.0, p = 0.0029), exploration training (F) (F 2, 31 = 7.524, p = 0.0022), exploration STM (G) (F2, 31 = 5.885, p = 0.0068) and exploration LTM (H) (F2, 31 = 5.044, p = 0.0127). Asterisks in panels (D)-(H) indicate values significantly different between groups (*p < 0.05, **p < 0.01, ***p < 0.001, Fisher’s LSD).

4. Discussion

BCI-838 (MGS0210) is a prodrug that is metabolized in liver into BCI-632 (MGS0039), the active metabolite delivered to brain. Its safety and tolerability have been evaluated through phase 1 human studies, which have found BCI-838 well tolerated in healthy subjects without serious adverse effects [7, 8].

Herein, we investigated effects of BCI-838 in PS19 transgenic mice [28], which develop an aging-related tauopathy without amyloid accumulation [28]. We chose ages of 3 and 7 months as representative of time points before tau pathology is present (3 months) and when the pathology is well established (7 months)[28]. Notably however, in this study, PS19 mice treated with vehicle exhibited abnormalities in NOR testing at 4 months of age suggesting that they were not truly presymptomatic. Indeed, Yoshiyama et al. [28] have documented synaptic loss and impaired synaptic function in 3-month old PS19 mice suggesting that even at this early age, initial manifestations of the disease are present.

BCI-838 treatment had no apparent adverse effects on animal health although it lessened weight loss seen in PS19 mice treated with vehicle. BCI-838 rescued impaired recognition memory in PS19 mice whether treatment was begun at 3 or 7 months of age.

Previously, we found that BCI-838 treatment improved learning behavior and reduced anxiety in Dutch (APPE693Q) transgenic (Tg) mice, an AD-related mouse model [18]. The most important result of the current study is to extend the potential utility of BCI-838 to a distinct set of neurodegenerative conditions that have tauopathy as part of their underlying basis. These disorders differ from AD in having distinct clinical presentations and pathological features [30]. A distinctive set of mutations also underlie familial cases [20] with PS19 mice expressing one of the mutations associated with FTLD [28]. While treatments have been described that ameliorate behavioral effects in amyloid or tau transgenic mouse models individually, we are not aware of any treatment that improves behavior in both, making mGluR2/3 antagonism perhaps a unique molecular target in neurodegenerative diseases that have both amyloid and tau as underlying pathologies.

Why an mGluR2/3 receptor antagonist might be effective in pathological states that involve both amyloidosis and tauopathy is unclear. mGluR2/3 receptors function primarily as presynaptic autoreceptors that (when stimulated) inhibit glutamate release [6]. One possibility is that BCI-838 is acting on some core glutamatergic defect found in Dutch Tg mice, blast-exposed rats and PS19 mice. Abnormalities in AMPA related glutamatergic neurotransmission are well established in human FTLD [1, 17]. In vivo imaging studies in PS19 mice have also found glutamate decreased in hippocampus [9, 10] and although not specifically studied in PS19 mice, other animal models of FTLD have suggested hypofunctional N-methyl-D-aspartate (NMDA) and AMPA receptors [1, 17]. How any of these abnormalities might be corrected by an mGluR2/3 antagonist is unclear.

Another possibility is that BCI-838 acts on some other core behavioral feature, which indirectly affects cognition. In rodents, mGluR2/3 receptor antagonists enhance learning while also possessing anxiolytic and antidepressant properties [3, 5, 15, 16, 24, 27]. As a class, they are regarded as promising treatments for a variety of mental health and neurological disorders including refractory depression[4]. Both Dutch Tg mice [18] and blast-exposed rats [21] exhibit features of anxiety, which might indirectly influence cognitive function. We are not aware of any reports that have examined PS19 mice for anxiety or depressive behavior. Future studies examining these traits in PS19 mice seem warranted [6].

Several study limitations should be mentioned. The experimental design did not include non-Tg wild type mice treated with BCI-838. The rationale for this exclusion was to limit animal usage to the minimum needed to achieve the experimental goal of determining the effects of BCI-838 on behavior in PS19 mice. In the design utilized (Fig. 1), we reasoned that comparison of the single group of vehicle treated non-Tg mice (Group 1) to vehicle treated PS19 mice (Group 2) served as a positive control for appearance of the transgene-related behavioral phenotype while comparison of the treated group (Group 3) to groups 1 and 2 measured the effectiveness of BCI-838 treatment. We note that in a previous study utilizing Dutch APP (APPE693Q) transgenic mice, while BCI-838 improved learning in BCI-838 treated Dutch APP mice, the drug had no effect on NOR or cued fear learning in non-Tg wild type mice [18]. However, it remains possible that BCI-838 may exert effects independent of simply reversing the impact of the tau mutation. To understand BCI-838’s potentially complex effects, the study of BCI-838 treated non-Tg mice will be essential.

This study is also limited by the restricted number of behavioral tests performed. Besides cognition, human tauopathies disturb mood, judgment, social interactions and other aspects of behavior and motor function [14], which were not assessed. NOR was chosen because cognitive deficits are well established in several lines of MAPT transgenic mice including PS19 mice [22, 23, 28, 29]. Now knowing effects of BCI-838 on NOR, extending these studies to other behavioral tests will be of interest. It will also be important to examine how BCI-838 affects tau related neuropathology and biochemistry as well as glutamatergic signaling which were not studied here.

The study also utilized a genetic model of tauopathy [28]. Most human tauopathies occur sporadically and whether the results reported here can be generalized to non-genetic causes of tauopathy or for that matter other genetic causes is unclear. In a separate study, we found that BCI-838 reversed post-traumatic stress disorder related behavioral traits in a rat model of blast-induced traumatic brain injury [21]. While the underlying pathophysiological basis for these traits remains to be fully understood, blast-exposed rats develop a tauopathy [12] raising the possibility that BCI-838 may be effective in states of pathological tau accumulation not driven by genetic tau mutations.

Another limitation of these studies is that they only included male mice, which reduces the generalizability of the findings. There indeed may be sex specific differences in response to BCI-838 and sex differences are known in survival, behavior, plasma cytokines and tau phosphorylation in the PS19 line [25]. Future studies in female mice will be important.

We also did not investigate length of treatment. The treatment course of one month was arbitrarily chosen based on previous studies in APP transgenic mice [18]. However, mGluR2/3 antagonists exert rapid behavioral effects in many experimental models [5, 13]. Thus, it remains possible that shorter durations of treatment might also be effective in PS19 mice.

5. Conclusion

These studies show that BCI-838 rescues recognition memory deficits in PS19 mice, which develop an age related tauopathy without amyloid accumulation. Effects were seen whether treatment was begun at 3 or 7 months of age. Taken in combination with a previous study showing that BCI-838 improved learning behavior and reduced anxiety in Dutch APP transgenic mice (APPE693Q), this work extends the potential spectrum of BCI-838’s therapeutic efficacy to neurodegenerative conditions that have both amyloidosis and tauopathy as part of their primary pathologies. It also suggests an mGluR2/3 dependent mechanism as a basis for the behavioral deficits in PS19 mice.

Highlights.

  • BCI-838 is an mGluR2/3 receptor antagonist pro-drug.

  • BCI-838 rescued deficits in object recognition memory in PS19 tauopathy mice.

  • Treatment was effective whether begun at 3 or 7 months of age.

  • mGluR2/3 dependent mechanisms underlie the behavioral deficits in PS19 mice.

Acknowledgements

The views expressed in this manuscript are those of the authors and do not necessarily reflect the position of the Department of the Veterans Affairs or the United States Government.

Funding

This work was supported by Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service awards 1I01RX000684 (SG), 1I01RX002333 (SG), 1I01RX002660 (GE), 1I01RX003846 (GE), and 1I21RX003459 (MAGS); Department of Veterans Affairs Office of Research and Development Medical Research Service award 1I01BX004067 (GE) and the Mount Sinai Alzheimer’s Disease Research Center P30 AG06614 (SG, MS)

Abbreviations:

AMPA

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

Aβ

Amyloid beta peptide

AD

Alzheimer’s disease

ANOVA

analysis of variance

BCI

Brain Cell Inc.

DI

discrimination index

FO

familiar object

FTLD

frontotemporal lobar degeneration

LTM

long term memory

mGluR2/3

metabotropic glutamate receptor 2/3

MAPT

microtubule associated protein

NMDA

N-methyl-D-aspartate

non-Tg

non transgenic

NO

novel object

NOR

novel object recognition

OB1

object 1

OB2

object 2

STM

short term memory

Tg

transgenic

veh

vehicle

Footnotes

CRediT authorship contribution statement

CB and FG identified the key pro-neurogenic action of BCI-838 and supplied the drug for these studies; MEE, SG, GPG, JTD and GE designed the study; GPG, JVHM, GMP and AO-P performed the experiments; GPG, BR, MB and GE analyzed data. GPG, MB, SG, MEE, JTD, JVHM, BSG, BR, MS and GE wrote the paper. All authors read and approved the final manuscript.

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Ethical statement

Studies were conducted in compliance with the US Public Health Service policy on the humane care and use of laboratory animals, all Federal regulations governing the protection of animals in research including the Animal Welfare Act and the principles set forth in the “Guide for Care and Use of Laboratory Animals,” Institute of Laboratory Animals Resources, National Research Council, National Academy Press, 2011. Experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the James J. Peters VA Medical Center (Bronx NY).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declaration of Competing interests

GPG, MB, JVHM, GMP, AOP, MAG, RDG, BR, FHG and GAE have no competing interests to declare. MS has served as a consultant for Bayer Schering Pharma, Bristol-Meyers Squibb, Elan Corporation, Genentech, Medivation, Medpace, Pfizer, Janssen, Takeda Pharmaceutical Company Limited, and United Biosource Corporation. She receives research support from the NIH. CB is a former employee of BrainCells Inc. BrainCells Inc provided drug and advice. MEE receives research support from the NIH, the XDP Foundation, and the Cure Alzheimer’s Fund. SG has served as a consultant for Diagenic and the Pfizer-Janssen Alzheimer’s Immunotherapy Alliance. He received research support from Warner-Lambert, Pfizer, Baxter Healthcare, Amicus and Avid. He served on the DSMB for an amyloid vaccine trial by Elan Pharmaceuticals. He receives research support from the VA, NIH, ADDF and the Cure Alzheimer’s Fund. SG and MEE have received compensation for chart review in the areas of cognitive neurology and pediatric neurology, respectively.

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