Common alterations in parallel metabolomic profiling of serum and spinal cord and mechanistic studies on neuropathic pain following PPARα administration.

Neuropathic pain (NP) is usually treated with analgesics and symptomatic therapy with poor efficacy and numerous side effects, highlighting the urgent need for effective treatment strategies. Recent studies have reported an important role for peroxisome proliferator-activated receptor alpha (PPARα) in regulating metabolism as well as inflammatory responses. Through pain behavioral assessment, we found that activation of PPARα prevented chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia. In addition, PPARα ameliorated inflammatory cell infiltration at the injury site and decreased microglial activation, NOD-like receptor protein 3 (NLRP3) inflammasome production, and spinal dendritic spine density, as well as improved serum and spinal cord metabolic levels in mice. Administration of PPARα antagonists eliminates the analgesic effect of PPARα agonists. PPARα relieves NP by inhibiting neuroinflammation and functional synaptic plasticity as well as modulating metabolic mechanisms, suggesting that PPARα may be a potential molecular target for NP alleviation. However, the effects of PPARα on neuroinflammation and synaptic plasticity should be further explored.

A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice. A 4-week systemic treatment of Mecp2 HET mice with LM22A-4 restored spine volume in MeCP2-expressing neurons to wild-type (WT) levels, whereas spine volume in MeCP2-lacking neurons remained comparable to that in neurons from female WT mice. Female Mecp2 HET mice engaged in aggressive behaviors more than WT mice, the levels of which were reduced to WT levels by the 4-week LM22A-4 treatment. These data provide additional support to the potential usefulness of novel therapies not only for RTT but also to other BDNF-related disorders.

Altered projection-specific synaptic remodeling and its modification by oxytocin in an idiopathic autism marmoset model.

Alterations in the experience-dependent and autonomous elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD), though it is unclear what synaptic traits are responsible. Here, utilizing a valproic acid-induced ASD marmoset model, which shares common molecular features with idiopathic ASD, we investigate changes in the structural dynamics of tuft dendrites of upper-layer pyramidal neurons and adjacent axons in the dorsomedial prefrontal cortex through two-photon microscopy. In model marmosets, dendritic spine turnover is upregulated, and spines are generated in clusters and survived more often than in control marmosets. Presynaptic boutons in local axons, but not in commissural long-range axons, demonstrate hyperdynamic turnover in model marmosets, suggesting alterations in projection-specific plasticity. Intriguingly, nasal oxytocin administration attenuates clustered spine emergence in model marmosets. Enhanced clustered spine generation, possibly unique to certain presynaptic partners, may be associated with ASD and be a potential therapeutic target.

Melatonin mitigates cisplatin-induced cognitive impairment in rats and improves hippocampal dendritic spine density.

Cisplatin-induced cognitive impairment (chemobrain) affects a considerable percentage of cancer patients and has no established pharmacological treatment. Chemobrain can be associated with neuroinflammation and oxidative stress. Melatonin, a pineal hormone, is known to have antioxidant, anti-inflammatory and neuroprotective potential. In this study, we investigated cisplatin-induced cognitive impairment in rats and whether melatonin can improve or reverse this impairment. Behavioral testing involved measuring working memory using the novel location recognition test (NLRT) under conditions of cisplatin or cisplatin + melatonin treatment, followed by the collection of rats' brains. The brains were subsequently stained with Golgi-Cox stain and then the hippocampus area CA3 of each one was examined, and dendritic spine density was calculated. Treatment with cisplatin resulted in deficits in the rats' performance in the NLRT (P < 0.05). These deficits were prevented by the coadministration of melatonin (P < 0.05). Cisplatin also reduced the density of dendritic spines in the hippocampus (P < 0.0001), specifically CA3 area, while the coadministration of melatonin significantly reversed this reduction (P < 0.001). This study showed that melatonin can ameliorate cisplatin-induced spatial memory deficits and dendritic spines density abnormalities in rats. Given that melatonin is a safe and wildly used supplement, it is feasible to explore its use as a palliative intervention in cancer treatment.

Histological and Memory Alterations in an Innovative Alzheimer's Disease Animal Model by Vanadium Pentoxide Inhalation.

Background: Previous work from our group has shown that chronic exposure to Vanadium pentoxide (V2O5) causes cytoskeletal alterations suggesting that V2O5 can interact with cytoskeletal proteins through polymerization and tyrosine phosphatases inhibition, causing Alzheimer's disease (AD)-like hippocampal cell death. Objective: This work aims to characterize an innovative AD experimental model through chronic V2O5 inhalation, analyzing the spatial memory alterations and the presence of neurofibrillary tangles (NFTs), amyloid-ß (Aß) senile plaques, cerebral amyloid angiopathy, and dendritic spine loss in AD-related brain structures. Methods: 20 male Wistar rats were divided into control (deionized water) and experimental (0.02 M V2O5 1 h, 3/week for 6 months) groups (n = 10). The T-maze test was used to assess spatial memory once a month. After 6 months, histological alterations of the frontal and entorhinal cortices, CA1, subiculum, and amygdala were analyzed by performing Congo red, Bielschowsky, and Golgi impregnation. Results: Cognitive results in the T-maze showed memory impairment from the third month of V2O5 inhalation. We also noted NFTs, Aß plaque accumulation in the vascular endothelium and pyramidal neurons, dendritic spine, and neuronal loss in all the analyzed structures, CA1 being the most affected. Conclusions: This model characterizes neurodegenerative changes specific to AD. Our model is compatible with Braak AD stage IV, which represents a moment where it is feasible to propose therapies that have a positive impact on stopping neuronal damage.

Manipulation of α4ßδ GABAA receptors alters synaptic pruning in layer 3 prelimbic prefrontal cortex and impairs temporal order recognition: Implications for schizophrenia and autism.

Temporal order memory is impaired in autism spectrum disorder (ASD) and schizophrenia (SCZ). These disorders, more prevalent in males, result in abnormal dendritic spine pruning during adolescence in layer 3 (L3) medial prefrontal cortex (mPFC), yielding either too many (ASD) or too few (SCZ) spines. Here we tested whether altering spine density in neural circuits including the mPFC could be associated with impaired temporal order memory in male mice. We have shown that α4ßδ GABAA receptors (GABARs) emerge at puberty on spines of L5 prelimbic mPFC (PL) where they trigger pruning. We show here that α4ßδ receptors also increase at puberty in L3 PL (P < 0.0001) and used these receptors as a target to manipulate spine density here. Pubertal injection (14 d) of the GABA agonist gaboxadol, at a dose (3 mg/kg) selective for α4ßδ, reduced L3 spine density by half (P < 0.0001), while α4 knock-out increased spine density âˆ¼ 40 % (P < 0.0001), mimicking spine densities in SCZ and ASD, respectively. In both cases, performance on the mPFC-dependent temporal order recognition task was impaired, resulting in decreases in the discrimination ratio which assesses preference for the novel object: -0.39 ± 0.15, gaboxadol versus 0.52 ± 0.09, vehicle; P = 0.0002; -0.048 ± 0.10, α4 KO versus 0.49 ± 0.04, wild-type; P < 0.0001. In contrast, the number of approaches was unaltered, reflecting unchanged locomotion. These data suggest that altering α4ßδ GABAR expression/activity alters spine density in L3 mPFC and impairs temporal order memory to mimic changes in ASD and SCZ. These findings may provide insight into these disorders.

Memory consolidation drives the enhancement of remote cocaine memory via prefrontal circuit.

Remote memory usually decreases over time, whereas remote drug-cue associated memory exhibits enhancement, increasing the risk of relapse during abstinence. Memory system consolidation is a prerequisite for remote memory formation, but neurobiological underpinnings of the role of consolidation in the enhancement of remote drug memory are unclear. Here, we found that remote cocaine-cue associated memory was enhanced in rats that underwent self-administration training, together with a progressive increase in the response of prelimbic cortex (PrL) CaMKII neurons to cues. System consolidation was required for the enhancement of remote cocaine memory through PrL CaMKII neurons during the early period post-training. Furthermore, dendritic spine maturation in the PrL relied on the basolateral amygdala (BLA) input during the early period of consolidation, contributing to remote memory enhancement. These findings indicate that memory consolidation drives the enhancement of remote cocaine memory through a time-dependent increase in activity and maturation of PrL CaMKII neurons receiving a sustained BLA input.

Bisphenol-A exposure leads to neurotoxicity through upregulating the expression of histone deacetylase 2 in vivo and in vitro.

Bisphenol-A (BPA), an environmental endocrine disruptor, is toxic to the central nervous system. Although recent studies have shown BPA-induced neurotoxicity, it is far from clear what precisely epigenetic mechanisms are involved in BPA-induced cognitive deficits. In this study, pheochromocytoma (PC12) cells were treated with BPA at 1 µM for 36 h in vitro. In vivo, C57BL/6 mice were administered to BPA at a dose of 1 mg/kg/day for 10 weeks. The results showed that 1 µM BPA exposure for 36 h impaired neurite outgrowth of PC12 cells through decreasing the primary and secondary branches. Besides, BPA exposure decreased the level of Ac-H3K9 (histone H3 Lys9 acetylation) by upregulating the expression of HDAC2 (histone deacetylases 2) in PC12 cells. Furthermore, treatment of both TSA (Trichostatin A, inhibitor of the histone deacetylase) and shHDAC2 plasmid (HDAC2 knockdown construct) resulted in amelioration neurite outgrowth deficits induced by BPA. In addition, it was shown that repression of HDAC2 could markedly rescue the spine density impairment in the hippocampus and prevent the cognitive impairment caused by BPA exposure in mice. Collectively, HDAC2 plays an essential role in BPA-induced neurotoxicity, which provides a potential molecular target for medical intervention.

Impact of Pharmacological and Non-Pharmacological Modulators on Dendritic Spines Structure and Functions in Brain.

Dendritic spines are small, thin, hair-like protrusions found on the dendritic processes of neurons. They serve as independent compartments providing large amplitudes of Ca2+ signals to achieve synaptic plasticity, provide sites for newer synapses, facilitate learning and memory. One of the common and severe complication of neurodegenerative disease is cognitive impairment, which is said to be closely associated with spine pathologies viz., decreased in spine density, spine length, spine volume, spine size etc. Many treatments targeting neurological diseases have shown to improve the spine structure and distribution. However, concise data on the various modulators of dendritic spines are imperative and a need of the hour. Hence, in this review we made an attempt to consolidate the effects of various pharmacological (cholinergic, glutamatergic, GABAergic, serotonergic, adrenergic, and dopaminergic agents) and non-pharmacological modulators (dietary interventions, enriched environment, yoga and meditation) on dendritic spines structure and functions. These data suggest that both the pharmacological and non-pharmacological modulators produced significant improvement in dendritic spine structure and functions and in turn reversing the pathologies underlying neurodegeneration. Intriguingly, the non-pharmacological approaches have shown to improve intellectual performances both in preclinical and clinical platforms, but still more technology-based evidence needs to be studied. Thus, we conclude that a combination of pharmacological and non-pharmacological intervention may restore cognitive performance synergistically via improving dendritic spine number and functions in various neurological disorders.

Phencynonate hydrochloride exerts antidepressant effects by regulating the dendritic spine density and altering glutamate receptor expression.

Phencynonate hydrochloride (PCH) is a drug that crosses the blood-brain barrier. Cellular experiments confirmed that PCH protects against glutamate toxicity and causes only weak central inhibition and limited side effects. As shown in our previous studies, PCH alleviates depression-like behaviours induced by chronic unpredictable mild stress (CUMS). Here we administered PCH at three different doses (4, 8 and 16 mg/kg) to male rats for two continuous days after CUMS and conducted behavioural tests to assess the dose-dependent antidepressant effects of PCH and its effects on the neuroplasticity in the hippocampus and medial prefrontal cortex (mPFC). Meanwhile, we measured the spine density and expression of related proteins to illustrate the mechanism of PCH. PCH treatment (8 mg/kg) significantly alleviated depression-like behaviours induced by CUMS. All doses of PCH treatment reversed the spine loss in prelimbic and CA3 regions induced by CUMS. Kalirin-7 expression was decreased in the hippocampus and mPFC of the CUMS group. The expression of the NR1 and NR2B subunits in the hippocampus, and NR2B in mPFC are increased by CUMS. PCH treatment (8 and 16 mg/kg) reversed all of these changes of Kalirin-7 in PFC and hippocampus, as well as NR1 and NR2B expression in the hippocampus. PCH is expected to be developed as a new type of rapid antidepressant. Its antidepressant effect may be closely related to the modulation of dendritic spine density in the prelimbic and CA3 regions and the regulation of Kalilin-7 and N-methyl-D-aspartic acid receptor levels in the hippocampus.

Prenatal exposure to di (2-ethylhexyl) phthalate causes autism-like behavior through inducing Nischarin expression in the mouse offspring.

Epidemiologic evidence has suggested a relationship between di (2-ethylhexyl) phthalate (DEHP) prenatal exposure and autism spectrum disorders (ASD), but the underlying mechanisms are still at large unknown. In this study, pregnant mice were intragastrically administered with DEHP once a day from GD 3 to GD 17 and the neurobehavioral changes of offspring were evaluated. In addition to the repetitive stereotyped behaviors, DEHP at the concentration of 50 mg/kg/day and above significantly impaired the sociability of the offspring (P < 0.05) and decreased the density of dendritic spines of pyramidal neurons in the prefrontal cortex (P < 0.05). At the same time, the expression of Nischarin protein in prefrontal lobe increased (P < 0.05). Similarly, after 12-h incubation of DEHP at the concentration of 100 nM, the total spine density, especially the mushroom and stubby spine populations, significantly decreased in the primary cultured prefrontal cortical neurons (P < 0.05). However, the inhibitory effect of DEHP were reversed by knockdown of Nischarin expression. Collectively, these results suggest that prenatal DEHP exposure induces Nischarin expression, causes dendritic spine loss, and finally leads to autism-like behavior in mouse offspring.

Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice.

Clinical evidence suggests that rapid and sustained antidepressant action can be attained with a single exposure to psychedelics. However, the biological substrates and key mediators of psychedelics' enduring action remain unknown. Here, we show that a single administration of the psychedelic DOI produces fast-acting effects on frontal cortex dendritic spine structure and acceleration of fear extinction via the 5-HT2A receptor. Additionally, a single dose of DOI leads to changes in chromatin organization, particularly at enhancer regions of genes involved in synaptic assembly that stretch for days after the psychedelic exposure. These DOI-induced alterations in the neuronal epigenome overlap with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder. Together, these data support that epigenomic-driven changes in synaptic plasticity sustain psychedelics' long-lasting antidepressant action but also warn about potential substrate overlap with genetic risks for certain psychiatric conditions.

NGPF2 triggers synaptic scaling up through ALK-LIMK-cofilin-mediated mechanisms.

Synaptic scaling is an extensively studied form of homeostatic plasticity critically involved in various brain functions. Although it is accepted that synaptic scaling is expressed through the postsynaptic accumulation of AMPA receptors (AMPARs), the induction mechanism remains elusive. In this study, we show that TTX treatment induces rapid but transient release of the neurite growth-promoting factor 2 (NGPF2), and this release is necessary and sufficient for TTX-induced scaling up. In addition, we show that inhibition of the anaplastic lymphoma kinase (ALK)-LIMK-cofilin signaling pathway blocks TTX- and NGPF2-induced synaptic scaling up. Furthermore, we show that TTX-induced release of NGPF2 is protein synthesis dependent and requires fragile X mental retardation protein 1 (FMRP1). These results indicate that activity blockade induces NGPF2 synthesis and release to trigger synaptic scaling up through LIMK-cofilin-dependent actin reorganization, spine enlargement, and stabilization of AMPARs at the synapse.

Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.

Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the extent and timescale of the impact in a mammalian brain are unknown. In this study, we used chronic two-photon microscopy to image longitudinally the apical dendritic spines of layer 5 pyramidal neurons in the mouse medial frontal cortex. We found that a single dose of psilocybin led to ∼10% increases in spine size and density, driven by an elevated spine formation rate. The structural remodeling occurred quickly within 24 h and was persistent 1 month later. Psilocybin also ameliorated stress-related behavioral deficit and elevated excitatory neurotransmission. Overall, the results demonstrate that psilocybin-evoked synaptic rewiring in the cortex is fast and enduring, potentially providing a structural trace for long-term integration of experiences and lasting beneficial actions.

PSD-95 protects synapses from ß-amyloid.

Beta-amyloid (Aß) depresses excitatory synapses by a poorly understood mechanism requiring NMDA receptor (NMDAR) function. Here, we show that increased PSD-95, a major synaptic scaffolding molecule, blocks the effects of Aß on synapses. The protective effect persists in tissue lacking the AMPA receptor subunit GluA1, which prevents the confounding synaptic potentiation by increased PSD-95. Aß modifies the conformation of the NMDAR C-terminal domain (CTD) and its interaction with protein phosphatase 1 (PP1), producing synaptic weakening. Higher endogenous levels or overexpression of PSD-95 block Aß-induced effects on the NMDAR CTD conformation, its interaction with PP1, and synaptic weakening. Our results indicate that increased PSD-95 protects synapses from Aß toxicity, suggesting that low levels of synaptic PSD-95 may be a molecular sign indicating synapse vulnerability to Aß. Importantly, pharmacological inhibition of its depalmitoylation increases PSD-95 at synapses and rescues deficits caused by Aß, possibly opening a therapeutic avenue against Alzheimer's disease.

Chronic AdipoRon Treatment Mimics the Effects of Physical Exercise on Restoring Hippocampal Neuroplasticity in Diabetic Mice.

Administration of exercise mimetic drugs could be a novel therapeutic approach to combat comorbid neurodegeneration and metabolic syndromes. Adiponectin is an adipocyte-secreted hormone. In addition to its antidiabetic effect, adiponectin mediates the antidepressant effect of physical exercise associated with adult hippocampal neurogenesis. The antidiabetic effect of the adiponectin receptor agonist AdipoRon has been demonstrated, but its potential pro-cognitive and neurotrophic effects in the hippocampus under diabetic condition are still unclear. This study reported that chronic AdipoRon treatment for 2 weeks improved hippocampal-dependent spatial recognition memory in streptozotocin-induced diabetic mice. Besides, AdipoRon treatment increased progenitor cell proliferation and neuronal differentiation in the hippocampal dentate gyrus (DG) of diabetic mice. Furthermore, AdipoRon treatment significantly increased dendritic complexity, spine density, and N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) in the dentate region, and increased BDNF levels in the DG of diabetic mice. AdipoRon treatment activated AMPK/PGC-1α signalling in the DG, whereas increases in cell proliferation and LTP were not observed when PGC-1α signalling was pharmacologically inhibited. In sum, chronic AdipoRon treatment partially mimics the benefits of physical exercise for learning and memory and hippocampal neuroplasticity in the diabetic brain. The results suggested that AdipoRon could be a potential physical exercise mimetic to improve hippocampal plasticity and hence rescue learning and memory impairment typically associated with diabetes.

Inhibiting Brd4 alleviated PTSD-like behaviors and fear memory through regulating immediate early genes expression and neuroinflammation in rats.

Post-traumatic stress disorder (PTSD) is characterized by depression/anxiety and memory failure, primarily fear memory. According to the reports, neuroinflammation and synaptic plasticity can play a role in the neurophysiological mechanisms underlying PTSD. Bromodomain-containing protein 4 (Brd4) intriguingly affects regulating of inflammatory responses and learning and memory. This study aimed to explore the effect of inhibiting Brd4 on depression/anxiety-like behaviors, spatial and fear memory, and underlying mechanisms in a model of PTSD. Inescapable foot shocks (IFS) with a sound reminder in 6 days were used to induce PTSD-like behaviors which were tested using contextual and cue fear tests, sucrose preference test, open-field test, elevated plus maze test, and Y-maze test. Meanwhile, the Brd4 inhibitor JQ1 was used as an intervention. The results found that IFS induced PTSD-like behaviors and indicated obvious Brd4 expression in microglia of the prefrontal cortex (PFC), hippocampus, and amygdala, pro-inflammatory cytokines over-expression, microglial activation, and nuclear factor-kappa B over-expression in PFC and hippocampus but not in amygdala. Meanwhile, the alterations of immediate early genes (IEGs) were found in PFC, hippocampus, and amygdala. Besides, dendritic spine density was reduced in PFC and hippocampus but was elevated in amygdala of rats with IFS. In addition, treatment with JQ1 significantly reduced freezing time in the contextual and cue fear test, reversed the behavioral impairment, decreased the elevated neuroinflammation, and normalized the alteration in IEGs and dendritic spine densities. The results suggested that Brd4 was involved in IFS-induced PTSD-like behaviors through regulating neuroinflammation, dynamics of IEGs, and synaptic plasticity.

Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down's syndrome mouse model.

Down syndrome (DS) is the most frequent genetic cause of intellectual disability including hippocampal-dependent memory deficits. We have previously reported hippocampal mTOR (mammalian target of rapamycin) hyperactivation, and related plasticity as well as memory deficits in Ts1Cje mice, a DS experimental model. Here we characterize the proteome of hippocampal synaptoneurosomes (SNs) from these mice, and found a predicted alteration of synaptic plasticity pathways, including long term depression (LTD). Accordingly, mGluR-LTD (metabotropic Glutamate Receptor-LTD) is enhanced in the hippocampus of Ts1Cje mice and this is correlated with an increased proportion of a particular category of mushroom spines in hippocampal pyramidal neurons. Remarkably, prenatal treatment of these mice with rapamycin has a positive pharmacological effect on both phenotypes, supporting the therapeutic potential of rapamycin/rapalogs for DS intellectual disability.

ABCC1 regulates cocaine-associated memory, spine plasticity and GluA1 and GluA2 surface expression.

ATP-binding cassettes C1 (ABCC1s) are expressed in the neurons of the brain, but their function in neurological diseases is far from clear. In this study, we investigated the role of ABCC1 in the hippocampus in cocaine-associated memory and spine plasticity. We also investigated the role of ABCC1 in AMPA receptors (AMPARs) surface expression in primary prefrontal cortex (PFC) neurons following dopamine treatment, which was used to mimic exposure to cocaine. We found that cocaine increased ABCC1 expression in the hippocampus, and ABCC1-siRNA blocked cocaine-induced place preference. Furthermore, a morphological study showed that ABCC1-siRNA reduced the total spine density, including thin, stubby and mushroom spines in both cocaine and basal treatments compared with controls. Meanwhile, in vitro tests showed that ABCC1-siRNA decreased GluA1 and GluA2 surface expression induced by dopamine, while a decreased number of synapses in primary PFC neurons was observed following dopamine treatment. The data show that ABCC1 in the hippocampus is critically involved in cocaine-associated memory and spine plasticity and that dopamine induces AMPARs surface expression in primary PFC neurons. ABCC1 is thus presented as a new signaling molecule involved in cocaine addiction, which may provide a new target for the treatment of cocaine addiction.

The effects of astaxanthin treatment on a rat model of Alzheimer's disease.

Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory loss and dementia, could be a consequence of the abnormalities of cortical milieu, such as oxidative stress, inflammation, and/or accompanied with the aggregation of ß-amyloid. The majority of AD patients are sporadic, late-onset AD, which predominantly occurs over 65 years of age. Our results revealed that the ferrous amyloid buthionine (FAB)-infused sporadic AD-like model showed deficits in spatial learning and memory and with apparent loss of choline acetyltransferase (ChAT) expression in medial septal (MS) nucleus. In hippocampal CA1 region, the loss of pyramidal neurons was accompanied with cholinergic fiber loss and neuroinflammatory responses including glial reaction and enhanced expression of inducible nitric oxide synthase (iNOS). Surviving hippocampal CA1 pyramidal neurons showed the reduction of dendritic spines as well. Astaxanthin (ATX), a potent antioxidant, reported to improve the outcome of oxidative-stress-related diseases. The ATX treatment in FAB-infused rats decreased neuroinflammation and restored the ChAT + fibers in hippocampal CA1 region and the ChAT expression in MS nucleus. It also partly recovered the spine loss on hippocampal CA1 pyramidal neurons and ameliorated the behavioral deficits in AD-like rats. From these data, we believed that the ATX can be a potential option for slowing the progression of Alzheimer's disease.