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ABSTRACT Amyloid β peptide (Aβ) has been thought to be neurotoxic and responsible for the impairment of learning and memory in Alzheimer's disease (AD). Humanin (HN), a 24 amino acid polypeptide first identified from the unaffected occipital lobe of an AD patient, is believed to be neuroprotective against the AD-related neurotoxicity. In this study, we investigated the neuroprotective effects of Colivelin (CLN), a novel HN derivative, against Aβ by using behavioral test, in vivo electrophysiological recording, and intracellular calcium imaging. Our results showed that intrahippocampal injection of CLN (0.2 nmol) effectively prevented Aβ25-35 (4 nmol)-induced deficits in spatial learning and memory of rats in Morris water maze test; the suppression of in vivo hippocampal long term potentiation (LTP) by Aβ25-35 was nearly completely prevented by CLN; in addition, CLN pretreatment also effectively inhibited Aβ25-35-induced calcium overload in primary cultured hippocampal neurons. These results indicate that CLN has significant neuroprotective properties against Aβ, and CLN may holds great promise for the treatment and prevention of AD. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Amyloid β protein (Aβ) is responsible for the deficits of learning and memory in Alzheimer's disease (AD). The high affinity between Aβ and nicotinic acetylcholine receptors (nAChRs) suggests that the impairment of cognitive function in AD might be involved in the Aβ-induced damage of nAChRs. This study investigated the effects of Aβ fragments on nAChR-mediated membrane currents in acutely isolated rat hippocampal pyramidal neurons by using whole-cell patch clamp technique. The results showed that: (1) nonspecific nAChR agonist nicotine, selective α7 nAChR agonist choline, and α4β2 nAChR agonist epibatidine all effectively evoked inward currents in CA1 neurons at normal resting membrane potential, with different desensitization characteristics; (2) acute application of different concentrations (pM-μM) of Aβ25-35, Aβ31-35, or Aβ35-31 alone did not trigger any membrane current, but pretreatment with 1 μM Aβ25-35 and Aβ31-35 similarly and reversibly suppressed the nicotine-induced currents; (3) further, choline- and epibatidine-induced currents were also reversibly suppressed by the Aβ pretreatment, but more prominent for the choline-induced response. These results demonstrate that the functional activity of both α7 and α4β2 nAChRs in the membrane of acutely isolated hippocampal neurons was significantly downregulated by Aβ treatment, suggesting that nAChRs, especially α7 nAChRs, in the brain may be the important biological targets of neurotoxic Aβ in AD. In addition, the similar suppression of nAChR currents by Aβ25-35 and Aβ31-35 suggests that the sequence 31-35 in Aβ molecule may be a shorter active center responsible for the neurotoxicity of Aβ in AD. Synapse, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The high density of senile plaques with amyloid beta protein (Aβ) and the loss of cholinergic neurons in the brain are the dominated pathological characteristics of Alzheimer's disease (AD). However, the active center of Aβ, especially the cholinergic mechanism underlying the Aβ neurotoxicity, is mostly unknown. This study examined the effects of different Aβ fragments on hippocampal long-term potentiation (LTP) and investigated its probable α7 nicotinic acetylcholine receptors (nAChRs) mechanism. The results show that: (1) intracerebroventicular injection of Aβ25-35 or Aβ31-35 significantly and similarly suppressed hippocampal LTP in CA1 region in rats; (2) choline, a selective α7 nAChR agonist, did not affect the LTP induction but enhanced LTP suppression induced by Aβ31-35; and (3) methyllycaconitine, a specific α7 nAChR antagonist, slightly suppressed hippocamal LTP but effectively prevented against Aβ31-35-induced LTP depression in the presence of Aβ31-35. These results indicate that: (1) the amino acid sequence 31-35 of the Aβ peptide might be a shorter active sequence in the full length molecule; (2) α7 nAChRs are required for the Aβ-induced suppression of hippocampal LTP. Thus, this study not only provides a new insight into the mechanism by which Aβ impairs synaptic plasticity but also strongly suggests that sequence 31-35 in Aβ molecule and α7 nAChRs in the brain might be potential therapeutic targets for the treatment of AD. Synapse 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Effects of fragment 31-35 of amyloid β-protein (AβP31-35) on the baseline synaptic transmission, shown as fEPSPs, and the long-term potentiation (LTP) induced by high-frequency stimuli (HFS) were investigated in vivo in the hippocampal CA1 region of rats; a longer fragment of AβP, i.e., AβP25-35, which had been generally accepted as the active center in AβP, was also tested comparatively along with AβP31-35. The results showed that: (1) the baseline fEPSPs induced by test stimuli were not changed by i.c.v. injection of AβP31-35, while application of either AβP31-35 or AβP25-35 with the same molar concentration (50 nmol) significantly and similarly suppressed the HFS-induced LTP; (2) higher concentration of AβP31-35 or longer time of AβP exposure exhibited stronger suppression on LTP, indicating a dose- and time-dependent trends; (3) no significant effects could be found on the paired-pulse facilitation (PPF) following AβP31-35 injection; (4) pretreatment with verapamil (2.5 mg/kg, i.p., 1 h prior to HFS), a blocker of L-type Ca2+ channels, did not affect the baseline fEPSPs, while it exhibited a significant suppression on LTP induced by HFS; and (5) surprisingly enough, coapplication with verapamil and AβP31-35 exhibited a similar suppression on LTP just as both of these two agents were used alone. These results indicate that: (1) AβP31-35, similar to AβP25-35, possesses potent suppressive effects on hippocampal LTP in vivo, supporting our proposal that the fragment AβP31-35 might be to date the shortest active sequence in full-length of AβP molecule; (2) AβP31-35-induced LTP suppression is not mediated by affecting the presynaptic processes; and (3) L-type Ca2+ channels might be one of the main pathways by which AβP31-35 insults LTP. Synapse 60:307-313, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid β (Aβ) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting, and ELISA were used to detect Aβ deposition, tau phosphorylation, and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aβ pathology, tau phosphorylation, and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) lacks effective clinical treatments. As the disease progresses, the cerebral glucose hypometabolism that appears in the preclinical phase of AD gradually worsens, leading to increasingly severe brain energy disorders. This review analyzes the brain energy deficit in AD and its etiology, brain energy rescue strategies based on ketone intervention, the effects and mechanisms of IF, the differences in efficacy between IF and ketogenic diet and the duality of IF. The evidence suggests that brain energy deficits lead to the development and progression of AD pathology. IF, which improves brain energy impairments by promoting ketone metabolism, thus has good therapeutic potential for AD. [ABSTRACT FROM AUTHOR]

Aims: Few treatments are available in the subacute phase of traumatic brain injury (TBI) except rehabilitation training. We previously reported that transient CO2 inhalation applied within minutes after reperfusion has neuroprotective effects against cerebral ischemia/reperfusion injury. In this study, it was hypothesized that delayed CO2 postconditioning (DCPC) starting at the subacute phase may promote neurological recovery of TBI. Methods: Using a cryogenic TBI (cTBI) model, mice received DCPC daily by inhaling 5%/10%/20% CO2 for various time‐courses (one/two/three cycles of 10‐min inhalation/10‐min break) at Days 3–7, 3–14 or 7–18 after cTBI. Beam walking and gait tests were used to assess the effect of DCPC. Lesion size, expression of GAP‐43 and synaptophysin, amoeboid microglia number and glia scar area were detected. Transcriptome and recombinant interferon regulatory factor 7 (Irf7) adeno‐associated virus were applied to investigate the molecular mechanisms. Results: DCPC significantly promoted recovery of motor function in a concentration and time‐course dependent manner with a wide therapeutic time window of at least 7 days after cTBI. The beneficial effects of DCPC were blocked by intracerebroventricular injection of NaHCO3. DCPC also increased puncta density of GAP‐43 and synaptophysin, and reduced amoeboid microglia number and glial scar formation in the cortex surrounding the lesion. Transcriptome analysis showed many inflammation‐related genes and pathways were altered by DCPC, and Irf7 was a hub gene, while overexpression of IRF7 blocked the motor function improvement of DCPC. Conclusions: We first showed that DCPC promoted functional recovery and brain tissue repair, which opens a new therapeutic time window of postconditioning for TBI. Inhibition of IRF7 is a key molecular mechanism for the beneficial effects of DCPC, and IRF7 may be a potential therapeutic target for rehabilitation after TBI. [ABSTRACT FROM AUTHOR]

Background: Most previous studies supported that the mammalian target of rapamycin (mTOR) is over-activated in Alzheimer's disease (AD) and exacerbates the development of AD. It is unclear whether the causal associations between the mTOR signaling-related protein and the risk for AD exist. Objective: This study aims to investigate the causal effects of the mTOR signaling targets on AD. Methods: We explored whether the risk of AD varied with genetically predicted AKT, RP-S6K, EIF4E-BP, eIF4E, eIF4A, and eIF4G circulating levels using a two-sample Mendelian randomization analysis. The summary data for targets of the mTOR signaling were acquired from published genome-wide association studies for the INTERVAL study. Genetic associations with AD were retrieved from the International Genomics of Alzheimer's Project. We utilized the inverse variance weighted as the primary approach to calculate the effect estimates. Results: The elevated levels of AKT (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) and RP-S6K (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) may decrease the AD risk. In contrast, the elevated eIF4E levels (OR = 1.805, 95% CI=1.002-1.174, p = 0.045) may genetically increase the AD risk. No statistical significance was identified for levels of EIF4-BP, eIF4A, and eIF4G with AD risk (p > 0.05). Conclusion: There was a causal relationship between the mTOR signaling and the risk for AD. Activating AKT and RP-S6K, or inhibiting eIF4E may be potentially beneficial to the prevention and treatment of AD. [ABSTRACT FROM AUTHOR]

• Exogenous orexin-A (OXA) aggravated cognitive deficits and LTP depression in 3xTg-AD mice. • OXA increased Aβ and tau pathologies in the brain in 3xTg-AD mice. • OXA increased Aβ levels by affecting the expression of BACE1 and NEP. • OXA aggravated the disturbance of the circadian locomotor rhythm in 3xTg-AD mice. Dementia is the main clinical feature of Alzheimer's disease (AD). Orexin has recently been linked to AD pathogenesis, and exogenous orexin-A (OXA) aggravates spatial memory impairment in APP/PS1 mice. However, the effects of OXA on other types of cognitive deficits, especially in 3xTg-AD mice exhibiting both plaque and tangle pathologies, have not been reported. Furthermore, the potential electrophysiological mechanism by which OXA affects cognitive deficits and the molecular mechanism by which OXA increases amyloid β (Aβ) levels are unknown. In the present study, the effects of OXA on cognitive functions, synaptic plasticity, Aβ levels, tau hyperphosphorylation, BACE1 and NEP expression, and circadian locomotor rhythm were evaluated. The results showed that OXA aggravated memory impairments and circadian rhythm disturbance, exacerbated hippocampal LTP depression, and increased Aβ and tau pathologies in 3xTg-AD mice by affecting BACE1 and NEP expression. These results indicated that OXA aggravates cognitive deficits and hippocampal synaptic plasticity impairment in 3xTg-AD mice by increasing Aβ production and decreasing Aβ clearance through disruption of the circadian rhythm and sleep-wake cycle. [ABSTRACT FROM AUTHOR]

[Display omitted] • Alzheimer's disease is linked to an increase in anxiety and depression. • The 3xtg mouse model of AD shows symptoms of depression. • KO of the MCU in mitochondria changed GABAergic signalling and BDNF levels. • KO mice showed reduced symptoms of anxiety and depression. Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by emotional disturbance, especially anxiety and depression. More and more evidence shows that the imbalance of mitochondrial Ca2+ (mCa2+) homeostasis has a close connection with the pathogenesis of anxiety and depression. The Mitochondrial Calcium Uniporter (MCU), a key channel of mCa2+ uptake, induces the imbalance of mCa2+ homeostasis and may be a therapeutic target for anxiety and depression of AD. In the present study, we revealed for the first time that MCU knockdown in hippocampal neurons alleviated anxious and depressive behaviors of APP/PS1/tau mice through elevated plus-maze (EPM), elevated zero maze (EZM), sucrose preference test (SPT) and tail suspension test (TST). Western blot analysis results demonstrated that MCU knockdown in hippocampal neurons increased levels of glutamate decarboxylase 67 (GAD67), vesicular GABA transporter (vGAT) and GABA A receptor α1 (GABRA1) and activated the PKA-CREB-BDNF signaling pathway. This study indicates that MCU inhibition has the potential to be developed as a novel therapy for anxiety and depression in AD. [ABSTRACT FROM AUTHOR]

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Anisomycin is a pyrrolidine antibiotic isolated from Streptomyces griseolus , which is an efficient anti-inflammatory agent that functions both in vivo and in vitro. However, it is not clear whether anisomycin can exert neuroprotective effect in AD. In the present study, anisomycin was intragastrically administrated to female triple-transgenic AD (3xTg-AD) model mice, then Morris water maze test was used to observe the long-term spatial memory of mice, the in vivo hippocampal field potential recording was performed to evaluate the synaptic plasticity, the Western blot and immunofluorescence were employed to detect pathological changes, and the bioinformatics analysis was used to predict the potential target of anisomycin exerting effects in AD. The results showed that anisomycin ameliorated the long-term spatial memory deficits, improved LTP depression and increased the expression of PSD-95, reduced the Aβ and tau pathologies, and alleviated the activation of microglia and astrocytes in the brains of 3xTg-AD mice. In addition, the results from bioinformatics analysis showed that the potential target of anisomycin focused on inflammatory pathway. These results indicated that anisomycin exerts neuroprotective effects in 3xTg-AD mice by alleviating neuroinflammation, but the potential mechanism of anisomycin exerting neuroprotective effects needs to be further investigated. [Display omitted] • Anisomycin improves cognitive dysfunction and synaptic plasticity in 3xTg-AD mice. • Anisomycin reduces Aβ and tau pathologies in the brains of 3xTg-AD mice. • Anisomycin exerts neuroprotective effects in AD by alleviating neuroinflammation. [ABSTRACT FROM AUTHOR]

Background: Cognitive deficit is mainly clinical characteristic of Alzheimer's disease (AD). Recent reports showed adiponectin and its analogues could reverse cognitive impairments, lower amyloid-β protein (Aβ) deposition, and exert anti-inflammatory effects in different APP/PS1 AD model mice mainly exhibiting amyloid plaque pathology. However, the potential in vivo electrophysiological mechanism of adiponectin protecting against cognitive deficits in AD and the neuroprotective effects of adiponectin on 3xTg-AD mice including both plaque and tangle pathology are still unclear.Objective: To observe the effects of adiponectin treatment on cognitive deficits in 3xTg-AD mice, investigate its potential in vivo electrophysiological mechanism, and testify its anti-inflammatory effects.Methods: Barnes maze test, Morris water maze test, and fear conditioning test were used to evaluate the memory-ameliorating effects of adiponectin on 3xTg-AD mice. In vivo hippocampal electrophysiological recording was used to observe the change of basic synaptic transmission, long-term potentiation, and long-term depression. Immunohistochemistry staining and western blot were used to observe the activation of microglia and astroglia, and the expression levels of proinflammatory factors and anti-inflammtory factor IL-10.Results: Adiponectin treatment could alleviate spatial memory and conditioned fear memory deficits observed in 3xTg-AD mice, improve in vivo LTP depression and LTD facilitation, inhibit overactivation of microglia and astroglia, decrease the expression of proinflammatory factors NF- κB and IL-1β, and increase the expression level of IL-10 in the hippocampus of 3xTg-AD mice.Conclusion: Adiponectin could ameliorate cognitive deficits in 3xTg-AD mice through improving in vivo synaptic plasticity impairments and alleviating neuroinflammation in the hippocampus of 3xTg-AD mice. [ABSTRACT FROM AUTHOR]

Abstract: Amyloid β protein (Aβ) is thought to be responsible for loss of memory in Alzheimer''s disease (AD). A significant decrease in [Arg8]-vasopressin (AVP) has been found in the AD brain and in plasma; however, it is unclear whether this decrease in AVP is involved in Aβ-induced impairment of spatial cognition and whether AVP can protect against Aβ-induced deficits in cognitive function. The present study examined the effects of intracerebroventricular (i.c.v.) injection of AVP on spatial learning and memory in the Morris water maze test and investigated the potential protective function of AVP against Aβ-induced impairment in spatial cognition. The results were as follows: (1) i.c.v. injection of 25nmol Aβ25 – 35 resulted in a significant decline in spatial learning and memory; (2) 1nmol and 10nmol, but not 0.1nmol, AVP injections markedly improved learning and memory; (3) pretreatment with 1nmol or 10nmol, but not 0.1nmol, AVP effectively reversed the impairment in spatial learning and memory induced by Aβ25 – 35; and (4) none of the drugs, including Aβ25 – 35 and different concentrations of AVP, affected the vision or swimming speed of the rats. These results indicate that Aβ25 – 35 could significantly impair spatial learning and memory in rats, and pretreatment with AVP centrally can enhance spatial learning and effectively prevent the behavioral impairment induced by neurotoxic Aβ25 – 35. Thus, the present study provides further insight into the mechanisms by which Aβ impairs spatial learning and memory, suggesting that up-regulation of central AVP might be beneficial in the prevention and treatment of AD. [Copyright &y& Elsevier]

Background: Alzheimer's disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs.Objective: To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD.Methods: A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers.Results: DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels.Conclusion: DA4-JC is a promising drug for the treatment of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function. Type 2 diabetes mellitus (T2DM) is an important risk factor for AD. Glucose-dependent insulinotropic polypeptide (GIP) has been identified to be effective in T2DM treatment and neuroprotection.Objective: The present study investigated the neuroprotective effects and possible mechanisms of DAla2GIP-Glu-PAL, a novel long-lasting GIP analogue, in APP/PS1 AD mice.Methods: Multiple behavioral tests were performed to examine the cognitive function of mice. In vivo hippocampus late-phase long-term potentiation (L-LTP) was recorded to reflect synaptic plasticity. Immunohistochemistry and immunofluorescence were used to examine the Aβ plaques and neuroinflammation in the brain. IL-1β, TNF-α, and cAMP/PKA/CREB signal molecules were also detected by ELISA or western blotting.Results: DAla2GIP-Glu-PAL increased recognition index (RI) of APP/PS1 mice in novel object recognition test, elevated spontaneous alternation percentage of APP/PS1 mice in Y maze test, and increased target quadrant swimming time of APP/PS1 mice in Morris water maze test. DAla2GIP-Glu-PAL treatment enhanced in vivo L-LTP of APP/PS1 mice. DAla2GIP-Glu-PAL significantly reduced Aβ deposition, inhibited astrocyte and microglia proliferation, and weakened IL-1β and TNF-α secretion. DAla2GIP-Glu-PAL also upregulated cAMP/PKA/CREB signal transduction and inhibited NF-κB activation in the hippocampus of APP/PS1 mice.Conclusion: DAla2GIP-Glu-PAL can improve cognitive behavior, synaptic plasticity, and central pathological damage in APP/PS1 mice, which might be associated with the inhibition of neuroinflammation, as well as upregulation of cAMP-/PKA/CREB signaling pathway. This study suggests a potential benefit of DAla2GIP-Glu-PAL in the treatment of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms. Methods: Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS. Results: TSA treatment not only reduced amyloid β (Aβ) plaques and soluble Aβ oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aβ pathology by TSA was attributed to the enhancement of Aβ clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited Aβ aggregation and promoted the phagocytosis of Aβ oligomers. Conclusions: These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment. [ABSTRACT FROM AUTHOR]

• Metformin treatment starting 3–5 d after cTBI improved functional recovery. • Metformin applied at 1–2 d after cTBI had no beneficial effect on functional recovery. • Metformin promoted axon regeneration after cTBI by activating central AMPK. • Metformin inhibited glial scar formation after cTBI by activating central AMPK. Accumulating evidence suggests that chronic metformin posttreatment offers potent neuroreparative effects against acute brain injury. However, in previous studies, metformin was not initially administered beyond 24 h postinjury, and the effects of delayed metformin treatment in traumatic brain injury (TBI) and other types of acute brain injury and the related mechanisms are unclear. To test this, male C57BL/6 mice received once daily metformin treatment (20, 50 or 100 mg/kg/d, i.p.) at day 1–14, day 1–2, day 1–10, day 3–10, day 5–12 or day 5–28 after cryogenic TBI (cTBI). The results showed that 100 mg/kg/d metformin administered at day 1–14 postinjury significantly promoted motor functional recovery in the beam walking and gait tests and reduced the infarct volume. Metformin (100 mg/kg/d) administered at day 1–10 or day 3–10 but not day 1–2 or day 5–12 after cTBI significantly improved motor functional outcomes at day 7 and 14, and reduced the infarct volume at day 14. Interestingly, the therapeutic time window was further expanded when the duration of metformin treatment starting at day 5 postinjury was extended to 2 weeks. Furthermore, compared with cTBI, the administration of metformin at day 3–10 or day 5–28 after cTBI significantly elevated the expression of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and growth associated protein 43 (an axonal regeneration marker) and the number of vascular branch points and decreased the area of glial scar and the number of amoeboid microglia in the peri-infarct area at day 14 or 28 postinjury. The above beneficial effects of metformin were blocked by the intracerebroventricular injection of the AMPK inhibitor compound C (40 μg/mouse/d). Our data provide the first evidence that metformin has a wide therapeutic time window for at least 5 days after cTBI, during which it can improve functional recovery by promoting tissue repair and inhibiting glial scar formation and microglial activation in a central AMPK-dependent manner. [ABSTRACT FROM AUTHOR]

Cognitive impairments and circadian rhythm disorders are the main clinical manifestations of Alzheimer's disease (AD). Orexin has been reported as abnormally elevated in the cerebrospinal fluid of AD patients, accompanied with cognitive impairments. Our recent research revealed that suvorexant, a dual orexin receptor antagonist, could improve behavioral circadian rhythm disorders in 9-month-old APP/PS1 mice. Here we further observed whether suvorexant could ameliorate the cognitive decline in APP/PS1 mice by using behavioral tests, and investigated the possible mechanisms by in vivo electrophysiological recording, western blot, and immunochemistry. The results showed that suvorexant treatment effectively ameliorated the cognitive impairments, alleviated in vivo hippocampal long-term potentiation suppression, restored the circadian phosphorylated CREB expression in the hippocampus, and reduced amyloid-β protein deposition in the hippocampus and cortex in APP/PS1 mice. These results indicate that the neuroprotective effects of suvorexant against AD are involved in the reduction of amyloid-β plaques, improvement of synaptic plasticity, and circadian expression of phosphorylated CREB, suggesting that suvorexant could be beneficial to the prevention and treatment of AD. • Suvorexant treatment ameliorates the cognitive impairments in APP/PS1 mice. • Suvorexant treatment alleviates in vivo hippocampal LTP suppression in APP/PS1 mice. • Suvorexant treatment restores the circadian rhythm of pCREB expression in the hippocampus in APP/PS1 mice. • Suvorexant treatment reduces Aβ deposition in the hippocampus and cortex in APP/PS1 mice. [ABSTRACT FROM AUTHOR]

Disorders of brain glucose metabolism is known to affect brain activity in neurodegenerative diseases including Alzheimer's disease (AD). Furthermore, recent evidence has shown an association between AD and type 2 diabetes. Numerous reports have found that glucagon-like peptide-1 (GLP-1) receptor agonists improve the cognitive behavior and pathological features in AD patients and animals, which may be related to the improvement of glucose metabolism in the brain. However, the mechanism by which GLP-1 agonists improve the brain glucose metabolism in AD patients remains unclear. In this study, we found that SIRT1 is closely related to expression of GLP-1R in hippocampus of 3xTg mice. Therefore, we used semaglutide, a novel GLP-1R agonist currently undergoing two phase 3 clinical trials in AD patients, to observe the effect of SIRT1 after semaglutide treatment in 3XTg mice and HT22 cells, and to explore the mechanism of SIRT1 in the glucose metabolism disorders of AD. The mice were injected with semaglutide on alternate days for 30 days, followed by behavioral experiments including open field test, new object recognition test, and Y-maze. The content of glucose in the brain was also measured by using 18FDG-PET-CT scans. We measured the expression of Aβ and tau in the hippocampus, observed the expression of GLUT4 which is downstream of SIRT1, and tested the Glucose oxidase assay (GOD-POD) and Hexokinase (HK) in HT22 cells. Here, we found in the 3xTg mouse model of AD and in cultured HT22 mouse neurons that SIRT1 signaling is involved in the impairment of glucose metabolism in AD. Semaglutide can increased the expression levels of SIRT1 and GLUT4 in the hippocampus of 3xTg mice, accompanied by an improvement in learning and memory, decreased in Aβ plaques and neurofibrillary tangles. In addition, we further demonstrated that semaglutide improved glucose metabolism in the brain of 3xTg mice in vitro, semaglutide promoted glycolysis and improved glycolytic disorders, and increased the membrane translocation of GLUT4 in cultured HT22 cells. These effects were blocked by the SIRT1 inhibitor (EX527). These findings indicate that semaglutide can regulate the expression of GLUT4 to mediate glucose transport through SIRT1, thereby improving glucose metabolism dysfunction in AD mice and cells. The present study suggests that SIRT1/GLUT4 signaling pathway may be an important mechanism for GLP-1R to promote glucose metabolism in the brain, providing a reliable strategy for effective therapy of AD. [Display omitted] • Semaglutide (Wegovy, Ozempic, Rybelsus) is an effective diabetes drug. • Semaglutide improved cognition in the 3xtg mouse model of AD. • The drug increases glucose utilization as shown in 18FDG-PET-CT. • The effect is dependent on the SIRT1/GLUT4 signaling pathway. [ABSTRACT FROM AUTHOR]

Exaggerated Ca2+ signaling might be one of primary causes of neural dysfunction in Alzheimer's disease (AD). And the intracellular Ca2+ overload has been closely associated with amyloid-β (Aβ)-induced endoplasmic reticulum (ER) stress and memory impairments in AD. Here we showed for the first time the neuroprotective effects of Xestospongin C (XeC), a reversible IP3 receptor antagonist, on the cognitive behaviors and pathology of APP/PS1 AD mice. Male APP/PS1-AD mice (n = 20) were injected intracerebroventricularly with XeC (3μmol) via Alzet osmotic pumps for four weeks, followed by cognition tests, Aβ plaque examination, and ER stress-related protein measurement. The results showed that XeC pretreatment significantly improved the cognitive behavior of APP/PS1-AD mice, raising the spontaneous alteration accuracy in Y maze, decreasing the escape latency and increasing the target quadrant swimming time in Morris water maze; XeC pretreatment also reduced the number of Aβ plaques and the overexpression of ER stress proteins 78 kDa glucose-regulated protein (GRP-78), caspase-12, and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) in the hippocampus of APP/PS1 mice. In addition, in vitro experiments showed that XeC effectively ameliorated Aβ1 - 42-induced early neuronal apoptosis and intracellular Ca2+ overload in the primary hippocampal neurons. Taken together, IP3R-mediated Ca2+ disorder plays a key role in the cognitive deficits and pathological damages in AD mice. By targeting the IP3 R, XeC might be considered as a novel therapeutic strategy in AD. [ABSTRACT FROM AUTHOR]

Highlights • Co-existence of α-syn and Aβ was found in the brain of APP/PS1 transgenic mice. • α-syn injection alleviated cognitive deficits in APP/PS1 transgenic mice. • α-syn injection reduced pathological biomarkers of APP/PS1 transgenic mice. Abstract Amyloid-β (Aβ) peptide and α-synuclein (α-syn) are major components of senile plaques in Alzheimer's disease (AD) and Lewy bodies in Parkinson's disease (PD), respectively. Co-occurrence of Aβ and α-syn in the senile brains of AD and LB diseases suggests interactions between the two proteins. However, the significance of the overlapping deposition, especially the effects of α-syn on the Aβ aggregation, still remains to be clarified. In the present study, we investigated the effects of α-syn pre-formed fibrils (PFFs) injection on the cognitive behaviors and Aβ deposition in the brain of APP/PS1 transgenic AD mice by using Morris water maze (MWM) test, immunohistochemistry and western blot techniques. We found that APP/PS1 transgenic mice exhibited an obvious elevation in the α-syn load, as well as Aβ deposition in the brain compared with wild type of C57 BL littermates. 5 months after cerebral injection of exogenous α-syn, MWM tests showed an alleviation in cognitive impairments in APP/PS1 mice; western blot and immunohistochemistry experiments also exhibited a significant reduction in Aβ level in the brain of APP/PS1 mice injected with α-syn. These results suggest that α-syn aggregated in the brain of AD may act as a protective factor and defend the brain tissue from early Aβ deposition and cognitive deficits. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. The early primary symptom of AD is the decline of memory ability, which gradually develops into complete dementia. Type 2 diabetes mellitus (T2DM) is an important risk factor of AD; and mimetics of the incretin hormone GLP-1 developed to treat diabetes are being tested as a novel therapeutic strategy for AD. In the present study, we reported for the first time the neuroprotective effects of a novel GLP-1/GIP dual agonist DA5-CH that activates the incretin hormone GLP-1 and GIP receptors in the APP/PS1 transgenic AD mouse model. We found that: (1) DA5-CH administration effectively improved working-memory and long-term spatial memory of 9-month-old AD mice in Y-maze and Morris water maze tests; (2) DA5-CH also reduced hippocampal amyloid senile plaques and phosphorylated tau protein levels; (3) DA5-CH basically reversed the deficits in hippocampal late-phase long-term potentiation; (4) DA5-CH up-regulated the levels of p-PI3K and p-AKT growth factor kinases and prevented excessive activation of p-GSK3β in the hippocampus of APP/PS1 mice. Therefore, the neuroprotection of DA5-CH in alleviating cognitive impairments and pathological damages might be associated with the improvement of hippocampal synaptic plasticity and activation of the PI3K/AKT signaling pathway. We propose that DA5-CH may be beneficial for the treatment of AD patients, especially those with T2DM or hyperglycemia. [ABSTRACT FROM AUTHOR]

Abstract: Type 2 diabetes mellitus (T2DM) is an important risk factor for Alzheimer's disease (AD). Glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) have been identified to be effective in T2DM treatment and neuroprotection. In this study, we further explored the effects of a novel unimolecular GLP‐1/GIP/Gcg triagonist on the cognitive behavior and cerebral pathology in the 7‐month‐old triple transgenic mouse model of AD (3xTg‐AD), and investigated its possible electrophysiological and molecular mechanisms. After chronic administration of the GLP‐1/GIP/Gcg triagonist (10 nmol/kg bodyweight, once daily, i.p.) for 30 days, open field, Y maze and Morris water maze tests were performed, followed by in vivo electrophysiological recording, immunofluorescence and Western blotting experiments. We found that the chronic treatment with the triagonist could improve long‐term spatial memory of 3xTg‐AD mice in Morris water maze, as well as the working memory in Y maze task. The triagonist also alleviated the suppression of long‐term potentiation (LTP) in the CA1 region of hippocampus. In addition, the triagonist significantly reduced hippocampal pathological damages, including amyloid‐β (Aβ) and phosphorylated tau aggregates, and upregulated the expression levels of S133p‐CREB, T286p‐CAMKII and S9p‐GSK3β in the hippocampus of the 3xTg‐AD mice. These results demonstrate for the first time that the novel GLP‐1/GIP/Gcg triagonist is efficacious in ameliorating cognitive deficits and pathological damages of 3xTg‐AD mice, suggesting that the triagonist might be potentially beneficial in the treatment of AD. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) has been identified as a high risk factor for Alzheimer's disease (AD). The impairment of insulin signaling has been found in AD brain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, normalises insulin signaling and acts as a neuroprotective growth factor. We have previously shown that the long-lasting GLP-1 receptor (GLP-1R) agonist lixisenatide plays an important role in memory formation, synaptic plasticity and cell proliferation of rats. In the follow-up study, we analysed the neuroprotective effect and mechanism of lixisenatide, injected for 60 days at 10 nmol/kg i.p. once daily in APP/PS1/tau female mice and C57BL/6J female mice (as control) aged 12 month. The results showed that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. The study demonstrated that GLP-1R agonists such as lixisenatide might have the potential to be developed as a novel therapy for AD. [ABSTRACT FROM AUTHOR]

[Display omitted] Alzheimer's disease (AD) is a progressive neurodegenerative disease that worsens with age. Long non-coding RNAs (lncRNAs) dysregulation and its associated competing endogenous RNA (ceRNA) network have a potential connection with the occurrence and development of AD. A total of 358 differentially expressed genes (DEGs) were screened via RNA sequencing, including 302 differentially expressed mRNAs (DEmRNAs) and 56 differential expressed lncRNAs (DElncRNAs). Anti-sense lncRNA is the main type of DElncRNA, which plays a major role in the cis and trans regulation. The constructed ceRNA network consisted of 4 lncRNAs (NEAT1 , LINC00365 , FBXL19-AS1 , RAI1-AS1719) and 4 microRNAs (miRNAs) (HSA-Mir-27a-3p , HSA-Mir-20b-5p , HSA-Mir-17-5p , HSA-Mir-125b-5p), and 2 mRNAs (MKNK2 , F3). Functional enrichment analysis revealed that DEmRNAs are involved in related biological functions of AD. The co-expressed DEmRNAs (DNAH11 , HGFAC , TJP3 , TAC1 , SPTSSB , SOWAHB , RGS4 , ADCYAP1) of humans and mice were screened and verified by real-time quantitative polymerase chain reaction (qRT-PCR). In this study, we analyzed the expression profile of human AD-related lncRNA genes, constructed a ceRNA network, and performed functional enrichment analysis of DEmRNAs between human and mice. The obtained gene regulatory networks and target genes can be used to further analyze AD-related pathological mechanisms to optimize AD diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Memory loss and cognition decline are the main clinical manifestations of Alzheimer's disease (AD). Amyloid β protein (Aβ) aggregated in the brain is one of the key pathological characteristics of AD and responsible for the deficits in learning and memory. It is reported that davunetide, an octapeptide derived from activity-dependent neuroprotective protein (ADNP), inhibited Aβ aggregation and Aβ-induced neurotoxicity. To further characterize the neuroprotective roles of davunetide and its possible mechanism, the present study investigated the effects of davunetide on Aβ1-42-induced impairments in spatial memory, synaptic plasticity and hippocampal AKT level. In Morris water maze (MWM) test, bilateral intrahippocampal injection of Aβ1-42 significantly increased escape latency and decreased target quadrant swimming time of rats, while three weeks of intranasal application of davunetide reversed the Aβ1-42-induced learning deficits and memory loss in a dose-dependent manner. In vivo field potentiation recording showed that Aβ1-42 suppressed long-term potentiation (LTP) of excitatory postsynaptic potential (fEPSP) in the hippocampal CA1 region of rats, while davunetide effectively blocked the suppression of LTP, without affecting paired-pulse facilitation (PPF). Western blotting experiments showed a significant decrease in the level of hippocampal p-AKT (Ser473), not total AKT, in Aβ1-42 only group, which was mostly antagonized by davunetide treatment. These findings demonstrate that davunetide, probably by enhancing PI3K/AKT pathway, plays an important positive role in attenuating Aβ1-42-induced impairments in spatial memory and synaptic plasticity, suggesting that davunetide could be an effective therapeutic candidate for the prevention and treatment of neurodegenerative disease such as AD. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus(T2DM) is a risk factor of Alzheimer’s disease (AD), which is most likely linked to impairments of insulin signaling in the brain. Hence, drugs enhancing insulin signaling may have therapeutic potential for AD. Lixisenatide, a novel long-lasting glucagon-like peptide 1 (GLP-1) analogue, facilitates insulin signaling and has neuroprotective properties. We previously reported the protective effects of lixisenatide on memory formation and synaptic plasticity. Here, we describe additional key neuroprotective properties of lixisenatide and its possible molecular and cellular mechanisms against AD-related impairments in rats. The results show that lixisenatide effectively alleviated amyloid β protein (Aβ) 25-35-induced working memory impairment, reversed Aβ25-35-triggered cytotoxicity on hippocampal cell cultures, and prevented against Aβ25-35-induced suppression of the Akt-MEK1/2 signaling pathway. Lixisenatide also reduced the Aβ25-35 acute application induced intracellular calcium overload, which was abolished by U0126, a specific MEK1/2 inhibitor. These results further confirmed the neuroprotective and cytoprotective action of lixisenatide against Aβ-induced impairments, suggesting that the protective effects of lixisenatide may involve the activation of the Akt-MEK1/2 signaling pathway and the regulation of intracellular calcium homeostasis. [ABSTRACT FROM AUTHOR]

Cognitive dysfunction is the main clinical manifestation of Alzheimer's disease (AD). Previous research found that elevated orexin level in the cerebrospinal fluid was closely related to the course of AD, and orexin-A treatment could increase amyloid β protein (Aβ) deposition and aggravate spatial memory impairment in APP/PS1 mice. Furthermore, recent research found that dual orexin receptor (OXR) antagonist might affect Aβ level and cognitive dysfunction in AD, but the effects of OX1R or OX2R alone is unreported until now. Considering that OX1R is highly expressed in the hippocampus and plays important roles in learning and memory, the effects of OX1R in AD cognitive dysfunction and its possible mechanism should be investigated. In the present study, selective OX1R antagonist SB-334867 was used to block OX1R. Then, different behavioral tests were performed to observe the effects of OX1R blockade on cognitive function of 3xTg-AD mice exhibited both Aβ and tau pathology, in vivo electrophysiological recording and western blot were used to investigate the potential mechanism. The results showed that chronic OX1R blockade aggravated the impairments of short-term working memory, long-term spatial memory and synaptic plasticity in 9-month-old female 3xTg-AD mice, increased levels of soluble Aβ oligomers and p-tau, and decreased PSD-95 expression in the hippocampus of 3xTg-AD mice. These results indicate that the detrimental effects of SB-334867 on cognitive behaviors in 3xTg-AD mice are closely related to the decrease of PSD-95 and depression of in vivo long-term potentiation (LTP) caused by increased Aβ oligomers and p-tau. • SB-334867 aggravates the cognitive impairments in 3xTg-AD mice. • SB-334867 exacerbates in vivo hippocampal LTP depression in 3xTg-AD mice. • SB-334867 down-regulates the expression level of PSD-95 in the hippocampus of 3xTg-AD mice. • SB-334867 increases the expression levels of Aβ oligomers and p-tau in the hippocampus of 3xTg-AD mice. [ABSTRACT FROM AUTHOR]

Aggregation of amyloid protein (A and progressive loss of memory are the main characteristics of Alzheimer's disease (AD). It is noteworthy that approximately 40% of AD patients have depressive symptom. The close correlation between cognitive deficits and mental depression suggests a possibility that antidepression treatment might be beneficial to cognitive improvement in AD. The present study, by using tail-suspension test (TST), forced swimming, alternative electro-stimulus Y maze test and immunohistochemistry, examined the neuroprotective effects of desipramine, a newer generation tricyclic antidepressants (TCA), and investigated its possible molecular mechanism. The results showed that: (1) intra-hippocampal injection of A induced depression-like behavior and associative learning deficits in mice, with an increased mean immobility time in tail-suspension and forced swimming test and an increased mean error times in Y maze test; (2) after treatment with desipramine (10mg/kg, i.p.), the average immobility time significantly decreased, from s in A group to s in A plus desipramine group () in TST and from s to s ( or 9, ) in forced swimming test, respectively;the mean error times of mice in Y maze test also significantly decreased, from in A group to in A plus desipramine group (, ); (3) desipramine administration significantly prevented against A-induced down-regulation of phosphorylated cAMP response element binding protein (p-CREB) in the hippocampus. These results indicate that A could concurrently mimic the depression-like behavior and working memory disorder in mice, while desipramine could effectively reverse both the deficits induced by A. The neuroprotection of desipramine may be involved in the up-regulation of p-CREB level in the hippocampus of mice. [ABSTRACT FROM AUTHOR]

β-Amyloid (Aβ) is the main component of amyloid plaques developed in the brain of patients with Alzheimer's disease (AD). The increasing burden of Aβ in the cortex and hippocampus is closely correlated with memory loss and cognition deficits in AD. Recently, leptin, a 16 kD peptide derived mainly from white adipocyte tissue, has been appreciated for its neuroprotective function, although less is known about the effects of leptin on spatial memory and synaptic plasticity. The present study investigated the neuroprotective effects of leptin against Aβ-induced deficits in spatial memory and in vivo hippocampal late-phase long-term potentiation (L-LTP) in rats. Y maze spontaneous alternation was used to assess short term working memory, and the Morris water maze task was used to assess long term reference memory. Hippocampal field potential recordings were performed to observe changes in L-LTP. We found that chronically intracerebroventricular injection of leptin (1 μg) effectively alleviated Aβ1–42 (20 μg)-induced spatial memory impairments of Y maze spontaneous alternation and Morris water maze. In addition, chronic administration of leptin also reversed Aβ1–42-induced suppression of in vivo hippocampal L-LTP in rats. Together, these results suggest that chronic leptin treatments reversed Aβ-induced deficits in learning and memory and the maintenance of L-LTP. [ABSTRACT FROM AUTHOR]

Abstract: Type 2 diabetes mellitus is a risk factor of Alzheimer''s disease (AD), most likely linked to an impairment of insulin signaling in the brain. Liraglutide, a novel long-lasting glucagon-like peptide 1 (GLP-1) analog, facilitates insulin signaling and shows neuroprotective properties. In the present study, we analyzed the effects of liraglutide on the impairment of learning and memory formation induced by amyloid-β protein (Aβ), and the probable underlying electrophysiological and molecular mechanisms. We found that (1) bilateral intrahippocampal injection of Aβ25–35 resulted in a significant decline of spatial learning and memory of rats in water maze tests, together with a serious depression of in vivo hippocampal late-phase long-term potentiation (L-LTP) in CA1 region of rats; (2) pretreatment with liraglutide effectively and dose-dependently protected against the Aβ25–35-induced impairment of spatial memory and deficit of L-LTP; (3) liraglutide injection also activated cAMP signal pathway in the brain, with a nearly doubled increase in the cAMP contents compared with control. These results strongly suggest that upregulation of GLP-1 signaling in the brain, such as application of liraglutide, may be a novel and promising strategy to ameliorate the learning and memory impairment seen in AD. [Copyright &y& Elsevier]

The novel neuroprotective action of Humanin (HN), especially its derivative [Gly14]-humanin (HNG), against Alzheimer's disease (AD)-related insults has been reported. However, it is still short of electrophysiological evidence for the protection of HN on synaptic plasticity, and the molecular mechanisms that underlie the neuroprotective function of HN remain largely unknown. The present study examined the effects of intracerebroventricular ( i.c.v.) injection of HNG on amyloid β (Aβ), a main constituent of senile plaques in the AD brain, induced suppression of long-term potentiation (LTP) in the rat hippocampal CA1 region in vivo and investigated the possible mechanism of HNG in LTP protection. We found that application of Aβ fragments 25-35 (Aβ25-35) and 31-35 (Aβ31-35) significantly inhibited high frequency stimulation-induced LTP, while HNG effectively prevented the suppression of LTP induced by Aβ fragments in a dose-dependent manner. After pretreatment with Genistein, a tyrosine kinase inhibitor, the protective action of HNG on LTP was nearly completely abolished. Therefore, the present study demonstrated for the first time that HNG could protect against the neurotoxic Aβ-induced hippocampal LTP impairment and the tyrosine kinase pathway was involved in the neuroprotective action of HNG, suggesting that HNG might be one of the promising candidates for the treatment of AD in the future. Synapse 64:83-91, 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

• Chronic sleep deprivation (SD) aggravates the cognitive impairments in APP/PS1 mice. • Chronic SD exacerbates in vivo hippocampal LTP suppression in APP/PS1 mice. • Chronic SD down-regulates the expression level of PSD-95 in the hippocampus of APP/PS1 mice. • Chronic SD increases Aβ deposition and microglia activation in the hippocampus of APP/PS1 mice. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits. Sleep deprivation (SD) could lead to memory deficits, and it was a candidate risk factor for AD. However, the effects of chronic SD on the cognitive functions of AD model mice and its possible mechanism are still unclear. In the present study, 8-month-old male APP/PS1 transgenic mice and wild type (WT) littermates were subjected to chronic SD by using the modified multiple platform method (MMPM), with 20 h of SD each day for 21 days. Then, the effects of chronic SD on cognitive functions in APP/PS1 mice were tested by using behavioral tests, the potential mechanisms were investigated by in vivo electrophysiological recording, western blot and immunochemistry. The results showed that chronic SD obviously aggravated the cognitive impairments, exacerbated in vivo hippocampal long-term potentiation (LTP) suppression, reduced the expression level of PSD95, increased amyloid-β (Aβ) protein deposition and overactivated microglia in the hippocampus of APP/PS1 mice. These results indicate that chronic SD exacerbates the cognitive deficits in APP/PS1 mice by accelerating the development of AD pathologies, reducing the expression of PSD95 and aggravating the LTP suppression in hippocampus. At the same time, chronic SD also impaired cognitive functions and synaptic plasticity in WT mice through down-regulating the level of PSD95 and activating microglia. These findings further clarify the electrophysiological and molecular mechanisms of exacerbated cognitive deficits in AD caused by chronic SD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease that severely affects the health and lifespan of the elderly worldwide. Recently, the correlation between AD and type 2 diabetes mellitus (T2DM) has received intensive attention, and a promising new anti-AD strategy is the use of anti-diabetic drugs. Oxyntomodulin (Oxm) is a peptide hormone and growth factor that acts on neurons in the hypothalamus. OXM activates glucagon-like peptide 1 (GLP-1) and glucagon (Gcg) receptors, facilitates insulin signaling and has neuroprotective effects against Aβ 1 – 42 -induced cytotoxicity in primary hippocampal neurons. Here, we tested the effects of the protease-resistant analogue (D-Ser2)Oxm on spatial memory and synaptic plasticity and the underlying molecular mechanisms in the APP/PS1 transgenic mouse model of AD. The results showed that (D-Ser2)Oxm not only alleviated the impairments of working memory and long-term spatial memory, but also reduced the number of Aβ plaques in the hippocampus, and reversed the suppression of hippocampal synaptic long-term potentiation (LTP). Moreover, (D-Ser2)Oxm administration significantly increased p-PI3K/p-AKT1 expression and decreased p-GSK3β levels in the hippocampus. These results are the first to show an in vivo neuroprotective role of (D-Ser2)Oxm in APP/PS1 mice, and this role involves the improvement of synaptic plasticity, clearance of Aβ and normalization of PI3K/AKT/GSK3β cell signaling in the hippocampus. This study suggests that (D-Ser2)Oxm holds promise for the prevention and treatment of AD. • We evaluated the neuroprotective actions of (D-Ser2) Oxm in a transgenic AD mouse model. • (D-Ser2) Oxm alleviated the impairments of working memory and long-term spatial memory in APP/PS1 mice. • (D-Ser2) Oxm reduced the number of Aβ plaques in the hippocampus of APP/PS1 mice. • (D-Ser2) Oxm reversed the suppression of hippocampal long-term potentiation in the APP/PS1 mice. • The neuroprotective role of (D-Ser2) Oxm may involve the maintenance of PI3K/AKT/GSK3β homeostasis. [ABSTRACT FROM AUTHOR]