The Alzheimer's Disease Neuroimaging Initiative and the role and contributions of the Private Partners Scientific Board (PPSB).

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) encompasses members from industry, biotechnology, diagnostic, and non-profit organizations that have until recently been managed by the Foundation for the National Institutes of Health (FNIH) and provided financial and scientific support to ADNI programs. In this article, we review some of the major activities undertaken by the PPSB, focusing on those supporting the most recently completed National Institute on Aging grant, ADNI3, and the impact it has had on streamlining biomarker discovery and validation in Alzheimer's disease. We also provide a perspective on the gaps that may be filled with future PPSB activities as part of ADNI4 and beyond. HIGHLIGHTS: The Private Partners Scientific board (PPSB) continues to play a key role in enabling several Alzheimer's Disease Neuroimaging Initiative (ADNI) activities. PPSB working groups have led landscape assessments to provide valuable feedback on new technologies, platforms, and methods that may be taken up by ADNI in current or future iterations.

Recovery of memory from infantile amnesia is developmentally constrained.

Episodic memories formed during infancy are rapidly forgotten, a phenomenon associated with infantile amnesia, the inability of adults to recall early-life memories. In both rats and mice, infantile memories, although not expressed, are actually stored long term in a latent form. These latent memories can be reinstated later in life by certain behavioral reminders or by artificial reactivations of neuronal ensembles activated at training. Whether the recovery of infantile memories is limited by developmental age, maternal presence, or contingency of stimuli presentation remains to be determined. Here, we show that the return of inhibitory avoidance memory in rats following a behavioral reactivation consisting of an exposure to the context (conditioned stimuli [CS]) and footshock (unconditioned stimuli [US]) given in a temporally unpaired fashion, is evident immediately after US and is limited by the developmental age at which the reactivations are presented; however, it is not influenced by maternal presence or the time interval between training and reactivation. We conclude that one limiting factor for infantile memory reinstatement is developmental age, suggesting that a brain maturation process is necessary to allow the recovery of a "lost" infantile memory.

Developmental changes in plasticity, synaptic, glia, and connectivity protein levels in rat basolateral amygdala.

The basolateral complex of amygdala (BLA) processes emotionally arousing aversive and rewarding experiences. The BLA is critical for acquisition and storage of threat-based memories and the modulation of the consolidation of arousing explicit memories, that is, the memories that are encoded and stored by the medial temporal lobe. In addition, in conjunction with the medial prefrontal cortex (mPFC), the BLA plays an important role in fear memory extinction. The BLA develops relatively early in life, but little is known about the molecular changes that accompany its development. Here, we quantified relative basal expression levels of sets of plasticity, synaptic, glia, and connectivity proteins in the rat BLA at various developmental ages: postnatal day 17 (PN17, infants), PN24 (juveniles), and PN80 (young adults). We found that the levels of activation markers of brain plasticity, including phosphorylation of CREB at Ser133, CamKIIα at Thr286, pERK1/pERK2 at Thr202/Tyr204, and GluA1 at Ser831 and Ser845, were significantly higher in infant and juvenile compared with adult brain. In contrast, age increase was accompanied by a significant augmentation in the levels of proteins that mark synaptogenesis and synapse maturation, such as synaptophysin, PSD95, SynCAM, GAD65, GAD67, and GluN2A/GluN2B ratio. Finally, we observed significant age-associated changes in structural markers, including MAP2, MBP, and MAG, suggesting that the structural connectivity of the BLA increases over time. The biological differences in the BLA between developmental ages compared with adulthood suggest the need for caution in extrapolating conclusions based on BLA-related brain plasticity and behavioral studies conducted at different developmental stages.

Developmental changes in plasticity, synaptic, glia, and connectivity protein levels in rat medial prefrontal cortex.

The medial prefrontal cortex (mPFC) plays a critical role in complex brain functions including decision-making, integration of emotional, and cognitive aspects in memory processing and memory consolidation. Because relatively little is known about the molecular mechanisms underlying its development, we quantified rat mPFC basal expression levels of sets of plasticity, synaptic, glia, and connectivity proteins at different developmental ages. Specifically, we compared the mPFC of rats at postnatal day 17 (PN17), when they are still unable to express long-term contextual and spatial memories, to rat mPFC at PN24, when they have acquired the ability of long-term memory expression and finally to the mPFC of adult rats. We found that, with increased age, there are remarkable and significant decreases in markers of cell activation and significant increases in proteins that mark synaptogenesis and synapse maturation. Furthermore, we found significant changes in structural markers over the ages, suggesting that structural connectivity of the mPFC increases over time. Finally, the substantial biological difference in mPFC at different ages suggest caution in extrapolating conclusions from brain plasticity studies conducted at different developmental stages.

Mechanisms of critical period in the hippocampus underlie object location learning and memory in infant rats.

Episodic memories in early childhood are rapidly forgotten, a phenomenon that is associated with "infantile amnesia," the inability of adults to remember early-life experiences. We recently showed that early aversive contextual memory in infant rats, which is in fact rapidly forgotten, is actually not lost, as reminders presented later in life reinstate a long-lasting and context-specific memory. We also showed that the formation of this infantile memory recruits in the hippocampus mechanisms typical of developmental critical periods. Here, we tested whether similar mechanisms apply to a nonaversive, hippocampal type of learning. We report that novel object location (nOL) learned at postnatal day 17 (PN17) undergoes the typical rapid forgetting of infantile learning. However, a later reminder reinstates memory expression. Furthermore, as for aversive experiences, nOL learning at PN17 engages critical period mechanisms in the dorsal hippocampus: it induces a switch in the GluN2A/2B-NMDA receptor ratio, and brain-derived neurotrophic factor injected bilaterally into the dorsal hippocampus immediately after training results in long-lasting memory expression. We conclude that in infancy the hippocampus plays a necessary role in processing episodic and contextual memories, including nonaversive ones, and matures through a developmental critical period.

Infantile Amnesia: A Critical Period of Learning to Learn and Remember.

Infantile amnesia, the inability of adults to recollect early episodic memories, is associated with the rapid forgetting that occurs in childhood. It has been suggested that infantile amnesia is due to the underdevelopment of the infant brain, which would preclude memory consolidation, or to deficits in memory retrieval. Although early memories are inaccessible to adults, early-life events, such as neglect or aversive experiences, can greatly impact adult behavior and may predispose individuals to various psychopathologies. It remains unclear how a brain that rapidly forgets, or is not yet able to form long-term memories, can exert such a long-lasting and important influence. Here, with a particular focus on the hippocampal memory system, we review the literature and discuss new evidence obtained in rats that illuminates the paradox of infantile amnesia. We propose that infantile amnesia reflects a developmental critical period during which the learning system is learning how to learn and remember.

From Memory Impairment to Posttraumatic Stress Disorder-Like Phenotypes: The Critical Role of an Unpredictable Second Traumatic Experience.

Arousal and stress critically regulate memory formation and retention. Increasing levels of stress produce an inverted U-shaped effect on cognitive performance, including the retention of explicit memories, and experiencing a severe stress during a traumatic event may lead to posttraumatic stress disorder (PTSD). The molecular mechanisms underlying the impairing effect of a severe stress on memory and the key contribution of traumatic experiences toward the development of PTSD are still unknown. Here, using increasing footshock intensities in an inhibitory avoidance paradigm, we reproduced the inverted U-shaped curve of memory performance in rats. We then show that the inverted U profile of memory performance correlates with an inverted U profile of corticosterone level in the circulation and of brain-derived neurotrophic factor, phosphorylated tropomyosin-receptor kinase B, and methyl CpG binding protein in the dorsal hippocampus. Furthermore, training with the highest footshock intensity (traumatic experience) led to a significant elevation of hippocampal glucocorticoid receptors. Exposure to an unpredictable, but not to a predictable, highly stressful reminder shock after a first traumatic experience resulted in PTSD-like phenotypes, including increased memory of the trauma, high anxiety, threat generalization, and resistance to extinction. Systemic corticosterone injection immediately after the traumatic experience, but not 3 d later, was sufficient to produce PTSD-like phenotypes. We suggest that, although after a first traumatic experience a suppression of the corticosterone-dependent response protects against the development of an anxiety disorder, experiencing more than one trauma (multiple hits) is a critical contributor to the etiology of PTSD.

Developmental changes in plasticity, synaptic, glia and connectivity protein levels in rat dorsal hippocampus.

Thus far the identification and functional characterization of the molecular mechanisms underlying synaptic plasticity, learning, and memory have not been particularly dissociated from the contribution of developmental changes. Brain plasticity mechanisms have been largely identified and studied using in vitro systems mainly derived from early developmental ages, yet they are considered to be general plasticity mechanisms underlying functions -such as long-term memory- that occurs in the adult brain. Although it is possible that part of the plasticity mechanisms recruited during development is then re-recruited in plasticity responses in adulthood, systematic investigations about whether and how activity-dependent molecular responses differ over development are sparse. Notably, hippocampal-dependent memories are expressed relatively late in development, and the hippocampus undergoes and extended developmental post-natal structural and functional maturation, suggesting that the molecular mechanisms underlying hippocampal neuroplasticity may actually significantly change over development. Here we quantified the relative basal expression levels of sets of plasticity, synaptic, glia and connectivity proteins in rat dorsal hippocampus, a region that is critical for the formation of long-term explicit memories, at two developmental ages, postnatal day 17 (PN17) and PN24, which correspond to a period of relative functional immaturity and maturity, respectively, and compared them to adult age. We found that the levels of numerous proteins and/or their phosphorylation, known to be critical for synaptic plasticity underlying memory formation, including immediate early genes (IEGs), kinases, transcription factors and AMPA receptor subunits, peak at PN17 when the hippocampus is not yet able to express long-term memory. It remains to be established if these changes result from developmental basal activity or infantile learning. Conversely, among all markers investigated, the phosphorylation of calcium calmodulin kinase II α (CamKII α and of extracellular signal-regulated kinases 2 (ERK-2), and the levels of GluA1 and GluA2 significantly increase from PN17 to PN24 and then remain similar in adulthood, thus representing correlates paralleling long-term memory expression ability.

Ubiquitin Associates with the N-Terminal Domain of Nerve Growth Factor: The Role of Copper(II) Ions.

Many biochemical pathways involving nerve growth factor (NGF), a neurotrophin with copper(II) binding abilities, are regulated by the ubiquitin (Ub) proteasome system. However, whether NGF binds Ub and the role played by copper(II) ions in modulating their interactions have not yet been investigated. Herein NMR spectroscopy, circular dichroism, ESI-MS, and titration calorimetry are employed to characterize the interactions of NGF with Ub. NGF1-14 , which is a short model peptide encompassing the first 14 N-terminal residues of NGF, binds the copper-binding regions of Ub (KD =8.6 10-5 m). Moreover, the peptide undergoes a random coil-polyproline type II helix structural conversion upon binding to Ub. Notably, copper(II) ions inhibit NGF1-14 /Ub interactions. Further experiments performed with the full-length NGF confirmed the existence of a copper(II)-dependent association between Ub and NGF and indicated that the N-terminal domain of NGF was a valuable paradigm that recapitulated many traits of the full-length protein.

A positive autoregulatory BDNF feedback loop via C/EBPß mediates hippocampal memory consolidation.

Little is known about the temporal progression and regulation of the mechanisms underlying memory consolidation. Brain-derived-neurotrophic-factor (BDNF) has been shown to mediate the maintenance of memory consolidation, but the mechanisms of this regulation remain unclear. Using inhibitory avoidance (IA) in rats, here we show that a hippocampal BDNF-positive autoregulatory feedback loop via CCAAT-enhancer binding protein ß (C/EBPß) is necessary to mediate memory consolidation. At training, a very rapid, learning-induced requirement of BDNF accompanied by rapid de novo translation controls the induction of a persistent activation of cAMP-response element binding-protein (CREB) and C/EBPß expression. The latter, in turn, controls an increase in expression of bdnf exon IV transcripts and BDNF protein, both of which are necessary and, together with the initial BDNF requirement, mediate memory consolidation. The autoregulatory loop terminates by 48 h after training with decreased C/EBPß and pCREB and increased methyl-CpG binding protein-2, histone-deacetylase-2, and switch-independent-3a binding at the bdnf exon IV promoter.

Adsorption of NGF and BDNF derived peptides on gold surfaces.

This study tackles the interaction between gold surfaces and two peptide fragments named NGF(1-14) and BDNF(1-12), able to mimic the proliferative activity of the nerve growth factor (NGF) and the brain derived neurotrophic factor (BDNF), respectively. The physical adsorption processes on the solid surface from both single and binary peptide solutions, at physiological and acid pH, were investigated by QCM-D and CD experiments, as well as by molecular dynamics calculations. The relevant physicochemical properties at the hybrid bio-interface, including peptide-surface interaction, conformational changes, hydrodynamic thickness, viscoelastic parameters, and competitive vs. synergic behaviour of the two peptide fragments towards the surface, were scrutinized. Biological assays with neuronal cells pointed to the maintenance of the biological activity of NGF(1-14) and BDNF(1-12) peptide molecules within the adlayers on the gold surface.

The neurobiological bases of memory formation: from physiological conditions to psychopathology.

The formation of long-term memories is a function necessary for an adaptive survival. In the last two decades, great progress has been made in the understanding of the biological bases of memory formation. The identification of mechanisms necessary for memory consolidation and reconsolidation, the processes by which the posttraining and postretrieval fragile memory traces become stronger and insensitive to disruption, has indicated new approaches for investigating and treating psychopathologies. In this review, we will discuss some key biological mechanisms found to be critical for memory consolidation and strengthening, the role/s and mechanisms of memory reconsolidation, and how the interference with consolidation and/or reconsolidation can modulate the retention and/or storage of memories that are linked to psychopathologies.

Zinc(II) interactions with brain-derived neurotrophic factor N-terminal peptide fragments: inorganic features and biological perspectives.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin essential for neuronal differentiation, growth, and survival; it is involved in memory formation and higher cognitive functions. The N-terminal domain of BDNF is crucial for the binding selectivity and activation of its specific TrkB receptor. Zn(2+) ion binding may influence BDNF activity. Zn(2+) complexes with the peptide fragment BDNF(1-12) encompassing the sequence 1-12 of the N-terminal domain of BDNF were studied by means of potentiometry, electrospray mass spectrometry, NMR, and density functional theory (DFT) approaches. The predominant Zn(2+) complex species, at physiological pH, is [ZnL] in which the metal ion is bound to an amino, an imidazole, and two water molecules (NH2, N(Im), and 2O(water)) in a tetrahedral environment. DFT-based geometry optimization of the zinc coordination environment showed a hydrogen bond between the carboxylate and a water molecule bound to zinc in [ZnL]. The coordination features of the acetylated form [AcBDNF(1-12)] and of a single mutated peptide [BDNF(1-12)D3N] were also characterized, highlighting the role of the imidazole side chain as the first anchoring site and ruling out the direct involvement of the aspartate residue in the metal binding. Zn(2+) addition to the cell culture medium induces an increase in the proliferative activity of the BDNF(1-12) peptide and of the whole protein on the SHSY5Y neuroblastoma cell line. The effect of Zn(2+) is opposite to that previously observed for Cu(2+) addition, which determines a decrease in the proliferative activity for both peptide and protein, suggesting that these metals might discriminate and modulate differently the activity of BDNF.

Copper, BDNF and Its N-terminal domain: inorganic features and biological perspectives.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that influences development, maintenance, survival, and synaptic plasticity of central and peripheral nervous systems. Altered BDNF signaling is involved in several neurodegenerative disorders including Alzheimer's disease. Metal ions may influence the BDNF activity and it is well known that the alteration of Cu(2+) homeostasis is a prominent factor in the development of neurological pathologies. The N-terminal domain of BDNF represents the recognition site of its specific receptor TrkB, and metal ions interaction with this protein domain may influence the protein/receptor interaction. In spite of this, no data inherent the interaction of BDNF with Cu(2+) ions has been reported up to now. Cu(2+) complexes of the peptide fragment BDNF(1-12) encompassing the sequence 1-12 of N-terminal domain of human BDNF protein were characterized by means of potentiometry, spectroscopic methods (UV/Vis, CD, EPR), parallel tempering simulations and DFT-geometry optimizations. Coordination features of the acetylated form, Ac-BDNF(1-12), were also characterized to understand the involvement of the terminal amino group. Whereas, an analogous peptide, BDNF(1-12)D3N, in which the aspartate residue was substituted by an asparagine, was synthesized to provide evidence on the possible role of carboxylate group in Cu(2+) coordination. The results demonstrated that the amino group is involved in metal binding and the metal coordination environment of the predominant complex species at physiological pH consisted of one amino group, two amide nitrogen atoms, and one carboxylate group. Noteworthy, a strong decrease of the proliferative activity of both BDNF(1-12) and the whole protein on a SHSY5Y neuroblastoma cell line was found after treatment in the presence of Cu(2+). The effect of metal addition is opposite to that observed for the analogous fragment of nerve growth factor (NGF) protein, highlighting the role of specific domains, and suggesting that Cu(2+) may drive different pathways for the BDNF and NGF in physiological as well as pathological conditions.

Probing the copper(II) binding features of angiogenin. Similarities and differences between a N-terminus peptide fragment and the recombinant human protein.

The angiogenin protein (hAng) is a potent angiogenic factor and its cellular activities may be affected by copper ions even if it is yet unknown how this metal ion is able to produce this effect. Among the different regions of hAng potentially able to bind copper ions, the N-terminal domain appears to be an ideal candidate. Copper(II) complexes of the peptide fragments encompassing the amino acid residues 4-17 of hAng protein were characterized by potentiometric, UV-vis, CD, and EPR spectroscopic methods. The results show that these fragments have an unusual copper(II) binding ability. At physiological pH, the prevailing complex species formed by the peptide encompassing the protein sequence 4-17 is [CuHL], in which the metal ion is bound to two imidazole and two deprotonated amide nitrogen atoms disposed in a planar equatorial arrangement. Preliminary spectroscopic (UV-vis, CD, and EPR) data obtained on the copper(II) complexes formed by the whole recombinant hAng protein, show a great similarity with those obtained for the N-terminal peptide fragments. These findings indicate that within the N-terminal domain there is one of the preferred copper(II) ions anchoring site of the whole recombinant hAng protein.

The inorganic perspective of nerve growth factor: interactions of Cu2+ and Zn2+ with the N-terminus fragment of nerve growth factor encompassing the recognition domain of the TrkA receptor.

There is a significant overlap between brain areas with Zn(2+) and Cu(2+) pathological dys-homeostasis and those in which the nerve growth factor (NGF) performs its biological role. The protein NGF is necessary for the development and maintenance of the sympathetic and sensory nervous systems. Its flexible N-terminal region has been shown to be a critical domain for TrkA receptor binding and activation. Computational analyses show that Zn(2+) and Cu(2+) form pentacoordinate complexes involving both the His4 and His8 residues of the N-terminal domain of one monomeric unit and the His84 and Asp105 residues of the other monomeric unit of the NGF active dimer. To date, neither experimental data on the coordination features have been reported, nor has one of the hypotheses according to which Zn(2+) and Cu(2+) may have different binding environments or the Ser1 α-amino group could be involved in coordination been supported. The peptide fragment, encompassing the 1-14 sequence of the human NGF amino-terminal domain (NGF(1-14)), blocked at the C terminus, was synthesised and its Cu(2+) and Zn(2+) complexes characterized by means of potentiometric and spectroscopic (UV/Vis, CD, NMR, and EPR) techniques. The N-terminus-acetylated form of NGF(1-14) was also investigated to evaluate the involvement of the Ser1 α-amino group in metal-ion coordination. Our results demonstrate that the amino group is the first anchoring site for Cu(2+) and is involved in Zn(2+) coordination at physiological pH. Finally, a synergic proliferative activity of both NGF(1-14) and the whole protein on SHSY5Y neuroblastoma cell line was found after treatment in the presence of Cu(2+). This effect was not observed after treatment with the N-acetylated peptide fragment, demonstrating a functional involvement of the N-terminal amino group in metal binding and peptide activity.

Value-Generating Exploratory Trials in Neurodegenerative Dementias.

Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.

Early life experiences selectively mature learning and memory abilities.

The mechanisms underlying the maturation of learning and memory abilities are poorly understood. Here we show that episodic learning produces unique biological changes in the hippocampus of infant rats and mice compared to juveniles and adults. These changes include persistent neuronal activation, BDNF-dependent increase in the excitatory synapse markers synaptophysin and PSD-95, and significant maturation of AMPA receptor synaptic responses. Inhibition of PSD-95 induction following learning impairs both AMPA receptor response maturation and infantile memory, indicating that the synapse formation/maturation is necessary for creating infantile memories. Conversely, capturing the learning-induced changes by presenting a subsequent learning experience or by chemogenetic activation of the neural ensembles tagged by learning matures memory functional competence. This memory competence is selective for the type of experience encountered, as it transfers within similar hippocampus-dependent learning domains but not to other hippocampus-dependent types of learning. Thus, experiences in early life produce selective maturation of memory abilities.

Copper complexes of synthetic peptides mimicking neurotrophin-3 enhance neurite outgrowth and CREB phosphorylation.

In this work we report on the synthesis and physiochemical/biological characterization of a peptide encompassing the first thirteen residues of neurotrophin-3 (NT-3). The protein capability to promote neurite outgrowth and axonal branching by a downstream mechanism that involves the increase of the cAMP response element-binding level (CREB) was found for the NT3(1-13) peptide, thus validating its protein mimetic behaviour. Since copper ions are also involved in neurotransmission and their internalization may be an essential step in neuron differentiation and CREB phosphorylation, the peptide and its copper complexes were characterized by potentiometric and spectroscopic techniques, including UV-visible, CD and EPR. To have a detailed picture of the coordination features of the copper complexes with NT3(1-13), we also scrutinized the two peptide fragments encompassing the shorter sequences 1-5 and 5-13, respectively, showing that the amino group is the main anchoring site for Cu(ii) at physiological pH. The peptide activity increased in the presence of copper ions. The effect of copper(ii) addition is more marked for NT3(1-13) than the other two peptide fragments, in agreement with its higher affinity for metal ions. Confocal microscopy measurements carried out on fluorescently labelled NT3(1-13) indicated that copper ions increase peptide internalization.

The Copper(II)-Assisted Connection between NGF and BDNF by Means of Nerve Growth Factor-Mimicking Short Peptides.

Nerve growth factor (NGF) is a protein necessary for development and maintenance of the sympathetic and sensory nervous systems. We have previously shown that the NGF N-terminus peptide NGF(1-14) is sufficient to activate TrkA signaling pathways essential for neuronal survival and to induce an increase in brain-derived neurotrophic factor (BDNF) expression. Cu2+ ions played a critical role in the modulation of the biological activity of NGF(1-14). Using computational, spectroscopic, and biochemical techniques, here we report on the ability of a newly synthesized peptide named d-NGF(1-15), which is the dimeric form of NGF(1-14), to interact with TrkA. We found that d-NGF(1-15) interacts with the TrkA-D5 domain and induces the activation of its signaling pathways. Copper binding to d-NGF(1-15) stabilizes the secondary structure of the peptides, suggesting a strengthening of the noncovalent interactions that allow for the molecular recognition of D5 domain of TrkA and the activation of the signaling pathways. Intriguingly, the signaling cascade induced by the NGF peptides ultimately involves cAMP response element-binding protein (CREB) activation and an increase in BDNF protein level, in keeping with our previous result showing an increase of BDNF mRNA. All these promising connections can pave the way for developing interesting novel drugs for neurodegenerative diseases.