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Aluminum oxide nanoparticles (nano-aluminum) have been known to be widespread in the environment for decades. Exposure to nano-aluminum may impair learning and memory, but the potential mechanism has not yet been elucidated. In neurons, efficient clearance of damaged mitochondria through mitophagy plays an important role in mitochondrial energy supply, neuronal survival, and health. However, abnormal mitophagy induces accumulation of damaged mitochondria, which induces cellular dysfunction, contributing to the impairment of learning and memory. It is currently unclear whether nano-aluminum interferes with the function of nerve cells through mitophagy, leading to learning and memory disorders. Institute of Cancer Research (ICR) female mice were randomly divided into four groups, and treated with normal saline (control) and 50 nm nano-aluminum at concentrations of 25, 50, and 75 mg/kg for 30 days. Our results showed that exposure to nano-aluminum impaired the spatial learning and memory of mice. Superoxide dismutase levels decreased, whereas the levels of malondialdehyde increased. Moreover, there were significant pathological changes in the ultra-structure and function of mitochondria. Finally, expression of autophagy-related proteins LC3-II and Beclin-1 was upregulated and p62 expression decreased, but the expression of apoptotic and necrosis-related proteins had no significant difference among groups. Our results suggest that learning and memory impairment induced by nano-aluminum could be related to mitophagy.

Epidemiological studies indicate that long-term occupational exposure to aluminum (Al) causes neurotoxicity and cognitive impairment. While the molecular underpinnings associated with workers’ cognitive impairment is unclear, one mechanism may involve Al-induced PI3K/Akt/mTOR activation and neuronal cell death, which impairs learning and memory in rats. Here, we sought to determine whether PI3K/Akt/mTOR is also associated with cognitive impairment in Al-exposed occupational workers. Cognitive function was screened by Mini-Mental State Examination (MMSE) and Clock-Drawing Test (CDT), and serum Al and PI3K/Akt/mTOR-associated gene expression was quantified. A negative correlation between serum Al and scores of MMSE and CDT was found, which might relate with downregulation of PI3K/Akt/mTOR. To determine the role of the PI3K/Akt/mTOR pathway cognitive function, we treated zebrafish with Al and observed a profound impairment in learning and memory. Increased brain Al levels was associated with decreased expression of PI3K/Akt/mTOR in Al-exposed zebrafish. Finally, rapamycin, an mTOR inhibitor, was added to isolate the role of mTOR specifically in the Al exposed zebrafish. The results suggested that Al induces learning and memory deficits by downregulating PI3K, Akt, and mTOR1 expression and inducing neuronal cell death like rapamycin group. This study indicates that aluminum exposure can cause cognitive impairment through PI3K/Akt/mTOR pathway, with mTOR activity being a critical player involved in this mechanism. Future studies are necessary to further characterize the role of PI3K/Akt/mTOR1 signaling in Al-induced neurocognitive decline among Al occupational workers. These findings draw attention to Al risk exposure among occupational workers and the need to implement novel safety and protective measures to mitigate neurocognitive health risks in the Al industrial workspace.

The aim of this study was to explore the influence of the neurotoxicity of nanoalumina on primarily cultured neurons. Normal control, particle size control, aluminum, micron-alumina, and nanoalumina at 50-nm and 13-nm particle sizes were included as subjects to evaluate the level of apoptosis, necrosis, and autophagy in primarily cultured neurons and further explore the mitophagy induced by nanoalumina. The results demonstrated that nanoalumina could induce neuronal cell apoptosis, necrosis, and autophagy, among which autophagy was the most notable. When the autophagy inhibitor was added to the nanoalumina-treated group, it significantly downregulated the protein expression levels of Beclin-1 and LC3II/LC3. Observation under a transmission electron microscope and a fluorescence microscope revealed mitophagy characteristics induced by nanoalumina. Additionally, the neurotoxicological effects induced by nanoalumina were more significant than those induced by aluminum and in a particle size-dependent manner.

Aluminum (Al) is considered one of the environmental risk factors for Alzheimer's disease (AD). The present study aims to establish a zebrafish AD model induced by Al and explore if necrostation-1 (Nec-1), a specific inhibitor of necroptosis, is effective in relieving learning and memory deficits in the zebrafish AD models. We treated adult zebrafish with aluminum trichloride at various doses for 1 month, followed by a T-maze test to evaluate learning and memory performance. Al concentration, levels of acetylcholine (Ach), and AD-related protein and gene expression in the brain tissue were evaluated in the zebrafish AD models. Our results demonstrated that in the brain tissue of Al-treated zebrafish, Al accumulated, Ach levels decreased, and AD-related genes and proteins increased. As a result, the learning and memory performance of Al-treated zebrafish was impaired. This suggested that a zebrafish AD model was established. To test the effect of Nec-1 on the zebrafish AD model, we added Nec-1 into the culture medium of the Al-treated adult zebrafish. The results demonstrated that Nec-1 could relive the learning and memory deficits, enhance Ach levels and the numbers of neural cells, and impact necroptosis-related gene expression. We concluded that Nec-1 could reverse Al-induced learning and memory impairment and had potential theoretical value in the zebrafish AD model.

Aluminum is a widespread environmental neurotoxicant that can induce Alzheimer's disease (AD)-like damage, such as neuronal injury and impairment of learning and memory. Several studies have shown that aluminum could reduce the synaptic plasticity, but its molecular mechanism remains unclear. In this study, rats were treated with aluminum maltol (Al(mal)3) to establish a toxic animal model and PMA was used to interfere with the expression of PKC. The Morris water maze and open field test were used to investigate the behavioral changes of the rats. Western blotting and RT-PCR were used to detect the expression levels of NMDAR subunits, PKC and CaMKII. The results showed that Al(mal)3 damaged learning and memory function and reduced anxiety in rats. During this process, the expression of PKC was downregulated and it inhibited the expression of NMDARs through the phosphorylation of CaMKII.

Aluminum demonstrates clear neurotoxicity and can cause Alzheimer's disease (AD)-like symptoms, including cognitive impairment. One toxic effect of aluminum is a decrease in synaptic plasticity, but the specific mechanism remains unclear. In this study, PC12 cells were treated with Al(mal)3 to construct a toxic cell model. (S)-3,5-Dihydroxyphenylglycine (DHPG), α-methyl-4-carboxyphenylglycine (MCPG), and mGluR1-siRNA were used to interfere with the expression of metabotropic glutamate receptor subtype 1 (mGluR1). Polymerase chain reaction and western blotting were used to investigate the expression of mGluR1, protein kinase C (PKC), and N-methyl-D-aspartate receptor (NMDAR) subunits. ELISA was used to detect PKC enzyme activity. In PC12 cells, mRNA and protein expressions of PKC and NMDAR subunits were inhibited by Al(mal)3. Aluminum may further regulate the expression of NMDAR1 and NMDAR2B through mGluR1 to regulate PKC enzyme activity, thereby affecting learning and memory functions. Furthermore, the results implied that the mGluR1-PKC-NMDAR signaling pathway may predominately involve positive regulation. These findings provide new targets for studying the neurotoxic mechanism of aluminum.

Epidemiological studies indicate that long-term occupational exposure to aluminum (Al) causes neurotoxicity and cognitive impairment. While the molecular underpinnings associated with workers' cognitive impairment is unclear, one mechanism may involve Al-induced PI3K/Akt/mTOR activation and neuronal cell death, which impairs learning and memory in rats. Here, we sought to determine whether PI3K/Akt/mTOR is also associated with cognitive impairment in Al-exposed occupational workers. Cognitive function was screened by Mini-Mental State Examination (MMSE) and Clock-Drawing Test (CDT), and serum Al and PI3K/Akt/mTOR-associated gene expression was quantified. A negative correlation between serum Al and scores of MMSE and CDT was found, which might relate with downregulation of PI3K/Akt/mTOR. To determine the role of the PI3K/Akt/mTOR pathway cognitive function, we treated zebrafish with Al and observed a profound impairment in learning and memory. Increased brain Al levels was associated with decreased expression of PI3K/Akt/mTOR in Al-exposed zebrafish. Finally, rapamycin, an mTOR inhibitor, was added to isolate the role of mTOR specifically in the Al exposed zebrafish. The results suggested that Al induces learning and memory deficits by downregulating PI3K, Akt, and mTOR1 expression and inducing neuronal cell death like rapamycin group. This study indicates that aluminum exposure can cause cognitive impairment through PI3K/Akt/mTOR pathway, with mTOR activity being a critical player involved in this mechanism. Future studies are necessary to further characterize the role of PI3K/Akt/mTOR1 signaling in Al-induced neurocognitive decline among Al occupational workers. These findings draw attention to Al risk exposure among occupational workers and the need to implement novel safety and protective measures to mitigate neurocognitive health risks in the Al industrial workspace.

Aluminum (Al) is an environmental neurotoxicant with a wide exposure, but the molecular mechanism underlying its toxicity remains unclear. We used RNA sequencing (RNA-seq) in the hippocampus of Al-treated rats to identify 96 upregulated and 652 downregulated mRNAs, and 37 dysregulated long non-coding (lnc)RNAs. Gene ontology analysis showed that dysregulated genes were involved in glial cell differentiation, neural transmission, and vesicle trafficking. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed clustering of differentially expressed mRNAs and lncRNA target genes in several pathways, including the "adenosine monophosphate-activated protein kinase signaling pathway," "extracellular matrix receptor interaction," "the phosphatidylinositol 3 kinase-protein kinase B signaling pathway," and "focal adhesion" signaling pathway. RNA-seq results were validated by reverse transcription (RT)-PCR. Additionally, Al induced changes to the number and morphology of glial cells in the hippocampus of rats, as shown by glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) immunochemistry. RT-PCR and western blotting validated the significant increase in expression of glial cell-related genes GFAP and SOX10 following Al exposure compared with control rats, consistent with RNA-seq results. Collectively, these results suggest that aberrant mRNAs and lncRNAs respond to Al neurotoxicity, and that glial cell-related genes play important roles in the Al neurotoxicity mechanism. These findings provide the basis for designing targeted approaches for the treatment or prevention of Al-induced neurotoxicity.

Aluminum (Al) is an environmental neurotoxin with extensive exposure by humans, but the molecular mechanism of its toxicity is still unclear. Several studies have indicated that exposure to aluminum can impair learning and memory function. The purpose of this study was to investigate the mechanism of LTP injury and the effect of aluminum exposure on related signal pathways. The results showed that the axonal dendrites of neurons in the hippocampal CA1 area of rats exposed to maltol aluminum showed neuritic beading and the dendritic spines were reduced. This resulted in dose-dependent LTP inhibition and led to impaired learning and memory function in rats. The PI3K-Akt-mTOR pathway may play a crucial role in this process.

The brain is one of organs vulnerable to aluminum insult. Aluminum toxicity is involved in neurobehavioral deficit, neuronal cell dysfunction, and death. The aim of this study are as follows: (1) to evaluate the repairing efficiency of Necrostatin-1 (Nec-1), a cell death inhibitor, and Z-VAD-FMK, a pan-caspase inhibitor, on Al-induced neurobehavioral deficit and neuronal cell death, in order to evidence the cell death inducing ability of aluminum, and (2) to primarily explore the possibility of treating neuronal cell loss-related disease, such as Alzheimer's disease, with Nec-1 and Z-VAD in Al-induced dementia animal model. We found Nec-1 and Z-VAD-FMK alone or in combination could reduce aluminum-induced learning and memory impairment in mice. Pathohistological results indicated that Nec-1 and Z-VAD-FMK can decrease Al-induced neuronal death cell. In addition, some cell death-associated proteins in cell death signal pathway were inhibited by Nec-1 and Z-VAD-FMK in Al-exposed mice. In conclusions, Nec-1 and Z-VAD-FMK can repair the injury of learning and memory induced by aluminum in mice. Furthermore, Nec-1 was more obvious to repair the injury of learning and memory function compared with Z-VAD-FMK. Nec-1 and Z-VAD-FMK can repair the Al-induced morphological injury of cell and reduce the amounts of dead cell, and repairing effects were more significant at higher doses. The effect of Nec-1 was stronger than Z-VAD-FMK, though their mechanism was different. The combination of them had the strongest effect. Our study evidenced Al-induced neuronal necroptosis and apoptosis existing in animal model and suggested potential therapeutic effects of Nec-1 and Z-VAD-FMK on neuronal cell death in neurodegenerative diseases.

A number of studies have indicated that aluminum (Al) exposure can impair learning and memory function. The ability of Al to inhibit hippocampal long-term potentiation (LTP) suggests the possibility of Al impairing synaptic plasticity. LTP is dependent on the externalization of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPAR). The protein kinase B (Akt) and glycogen synthase kinase-3β (GSK-3β) signaling pathway has been demonstrated to mediate AMPAR delivery. A mechanism by which caspase-3 cleaves Akt is involved in synaptic plasticity, but the underlying molecular mechanism involved has still not been elucidated. The purpose of this study was to investigate the mechanism of LTP impairment and the related signaling pathway disturbance induced by Al exposure. Our results reveal that Al treatment produces a dose-dependent suppression of LTP and decreases in the AMPAR subunits GluR1 and GluR2, in both membrane and total cell extracts. Al caused increased accumulation of active caspase-3 and a gradual decrease in Akt and pGSK-3β. Interestingly, Al depressed LTP and AMPAR protein concentration. N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (a caspase-3 inhibitor) reversed the Al-induced LTP inhibition, increased levels of active caspase-3, and decreased AMPAR levels in both total and membrane-enriched extracts. It also decreased Akt and pGSK-3β. The molecular mechanism of Al-induced LTP impairment might be related to the activation of caspase-3, cleavage of Akt, activation of GSK-3β, and inhibition of the externalization of AMPAR.

Aluminum (Al) exposure impairs learning and memory function in humans and in animal models. Several studies have shown that the neurotoxicity of Al is associated with damage to mitochondrial morphology and mitochondrial dysfunction, but the molecular mechanism is unclear. The present study was performed to elucidate the possible molecular mechanism related to the Al-induced abnormal mitochondrial dynamics that lead to learning and memory disorders. SD rats were exposed to Al-maltolate complex (Al(mal)3) (blank, 0, 0.41, 0.81, or 1.62 mg/kg) for 30, 60, or 90 days, and neurobehavior, mitochondrial morphology, mitochondrial function, the levels of fission proteins such as dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1), and the levels of fusion proteins such as optic atrophy 1 (Opa1), mitofusin 1 (Mfn1), and mitofusin 2 (Mfn2) were explored. The results indicated that exposure to Al(mal)3 increased the concentration of Al in the brain in a time- and dose-dependent manner and impaired spatial learning and memory. Al(mal)3 damaged mitochondrial morphology and impaired mitochondrial function in the hippocampus. Dose-dependent elevations in the levels of mitochondrial fission (Drp1 and Fis1) and fusion (Opa1, Mfn1, and Mfn2) proteins were observed. In addition, the upregulation of calcineurin (CaN) and the reduced phosphorylation of Drp1 (s637) may have disturbed the balance of mitochondrial fission and fusion in the hippocampus. These results showed that Al-induced learning and memory impairment may be related to mitochondrial fission and fusion disorders.

As a representative substance of the polycyclic aromatic hydrocarbons, benzo[a]pyrene (B[a]P) is a widely distributed environmental contaminant. Several studies have indicated that B[a]P exposure could impair learning and memory function in human population and animal models. Abnormal hyperphosphorylation and aggregation of microtubule-associated protein tau play a crucial role in neurodegenerative diseases manifesting deficits of learning and memory. In the present study, we investigated the involvement of tau hyperphosphorylation in memory impairment after espousing to B[a]P in SD rats. Male SD rats were randomly divided into five groups: the blank control group received no treatment and the others received intraperitoneal injection of B[a]P (0, 1.0, 2.5, 6.25 mg/kg bw) for 1, 2, and 3 months, respectively. Morris water maze was employed to observe the learning and memory impairment. To find the relationship between cognitive functions and tau protein, we measured the site-specific phosphorylation of tau at Ser199, Ser396, Thr181, and Thr231, which are related with spatial and memory deficits in the brain of rats. The spatial and learning of rats were impaired after exposing to B[a]P for 1 month, so as 2 and 3 months compared to blank control groups, respectively. Rats exposed to 2.5 and 6.25 mg/kg bw B[a]P for either 2 or 3 months had modified behavior compared to control as indicated by the increased latencies, increased the first time arriving at the target space and decreased number crossing the platform and time in target quadrant. B[a]P led to tau hyperphosphorylation at Ser199, Thr181, and Thr231 epitopes. And with time and dose expanded, tau protein, Ser199, Thr181, and Thr231 expression increased. However, the differences in expression of Ser396 at different doses or points were not statistically significant. Moreover, we observed a correlation between memory impairments and tau phosphorylation levels. The present results indicate that Tau hyperphosphorylation is associated with the observed deficits in spatial learning and memory following exposure to B[a]P in SD rats.

Aluminum (AI), a known neurotoxin, has been implicated in Alzheimer’s Disease (AD), Amyotrophic Lateral Selerosis (ALS), Parkinsonism Dementia Complex, etc., and it causes extensive damage to the nervous system, including the impairment of learning and memory. However, to date, the mechanism of Al neurotoxicity has not been fully elucidated. Neuronal apoptosis has become a focus of interest, as it has been reported to play a key role in the impairment of learning and memory processes (Thompson,Science 267:1456, 1995). The Bcl-2 gene acts as an important effector for inhibiting apoptosis. In the present study we observe neuronal apoptosis in association with learning and memory impairment, as well as regional brain alterations in Bcl-2 expression in rats chronically exposed to Al. The chronic Al-intoxicated model was established by i.p. injection of AlCl3 in adult Sprague Dawley rats for 3 successive days, with one-day intervals, for 60 days. After exposure, the step-down test was performed to examine the behavioral reaction of the rats. Neuronal apoptosis and Bcl-2 protein expression in different regions of rat brain were then assessed by an immunohistochemical method. In the step-down test, the latency of Al-exposed rats was significantly lower than that of controls. Also, the number of performance errors in 5 minutes of exposure was significantly higher than that of controls. Neuronal apoptosis was extensive in the brain of Al-exposed groups, and the expressions of Bcl-2 protein in frontal cortex, cerebellum and hippocampus of Al-exposed rats was stronger. In conclusion, chronic Al-exposure in rats is associated with neuronal apoptosis in brain, and impaired learning and memory. Augmented Bcl-2 protein expression may be a stimulated compensatory mechanism.