calpain and Memory-Disorders

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Asymptomatic Diseases; Autopsy; Calpain; Case-Control Studies; Disease Models, Animal; Humans; Intelligence Tests; Male; Memory Disorders; Mice; Mice, Transgenic; Neocortex; Neuronal Plasticity; Neurons; Plaque, Amyloid; Primary Cell Culture; Synapses; Synaptic Transmission; Synaptosomes

Topics: Animals; Calcium; Calpain; Caspase 3; Cell Proliferation; Cognition Disorders; Hippocampus; Humans; Lithium Carbonate; Memory Disorders; Mice; Mice, Inbred C57BL; Neural Stem Cells; Paclitaxel

Sevoflurane is one of the most commonly used volatile anesthetics and it has been shown to induce widespread apoptotic neurodegeneration in aged rat. Calpain is also activated during apoptosis in several types of cells. We hypothesized that calpain resulted in apoptosis under long time sevoflurane exposure, and it might play a role in the sevoflurane-induced memory impairment in aged rats.. Seventy-two 18-month-old male Sprague-Dawley rats were randomly divided into three groups (n = 24): Control group rats were exposed to simply humid 50 % O2 balanced by N2 for 3 h; While M group rats received calpain inhibitor 10 mg/kg via the tail vein intravenously at 30 min before the animals inhaled 3 % sevoflurane for 3 h, subsequently received MDL 28170 3.33 mg/kg/h for 3 h. Sev group rats were only exposed to 3 % sevoflurane for 3 h without calpain inhibitor. Morris Water Maze was used to test the ability of learning and memory. Cytosolic calcium concentration was measured by using flow cytometry. Annexin-V labeled with a fluorophore or biotin can identify apoptotic cells by binding to PS. The expression of calpain in the hippocampus of rats was tested by Western blots.. The results showed that the M group had a shorter latency and had a larger number of times crossing over the previous platform site than that of the Sev group. Compared with Sev group, apoptosis rate and 76/80 kDa ratio of μ-calpain were significantly decreased in M group on the 1st day.. Sevoflurane might induce apoptosis through increasing [Ca(2+)]c and the activity of μ-calpain, which might be identified at least partially the molecular mechanism by which sevoflurane induces apoptosis.

Topics: Animals; Apoptosis; Blotting, Western; Calpain; Hippocampus; Male; Maze Learning; Memory; Memory Disorders; Methyl Ethers; Rats; Rats, Sprague-Dawley; Sevoflurane

Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is activated during aging and proteolytically degrades tau, abolishes its microtubule assembly function, induces tau aggregation and triggers neurodegeneration. AEP is upregulated and active during aging and is activated in human AD brain and tau P301S-transgenic mice with synaptic pathology and behavioral impairments, leading to tau truncation in NFTs. Tau P301S-transgenic mice with deletion of the gene encoding AEP show substantially reduced tau hyperphosphorylation, less synapse loss and rescue of impaired hippocampal synaptic function and cognitive deficits. Mice infected with adeno-associated virus encoding an uncleavable tau mutant showed attenuated pathological and behavioral defects compared to mice injected with adeno-associated virus encoding tau P301S. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases.

Topics: Aged; Aging; Alzheimer Disease; Amino Acid Sequence; Animals; Asparagine; Brain; Calpain; Caspases; Cognition; Cysteine Endopeptidases; Gene Knockout Techniques; HEK293 Cells; Humans; Memory Disorders; Mice, Transgenic; Molecular Sequence Data; Neurofibrillary Tangles; Neurotoxins; Phosphorylation; Protein Structure, Tertiary; Solubility; Synapses; tau Proteins; Up-Regulation

In the central nervous system, two calpain isoforms are highly expressed: calpain1 and calpain2. Here, we show for the first time that activation of the calpain isoform, calpain2, is a necessary event in hippocampal synaptic plasticity and in learning and memory. We developed a fluorescence resonance energy transfer-based animal model to monitor in vivo calpain activation in single cells and in real time. Additionally, utilizing a novel rabies virus glycoprotein-chimeric peptide, which enabled the transvascular delivery of small interfering RNA to the brain against calpain2, we down-regulated the calpain2 isoform in vivo. Calpain2 gene silencing eliminated long-term potentiation and impaired learning and memory. Our results not only identify the calpain2 isoform as a critical mediator in learning and memory but also highlight an innovative, highly efficient calpain2-targeting peptide capable of isoform-specific gene silencing in the brain. We anticipate these innovative technologies and our better understanding of the calpain machinery, particularly of the calpain2 isoform, will have substantial influence on future translational studies, attracting considerable interest in the use of calpain models and calpain-specific inhibitors in the development of therapeutics.

Topics: Amino Acid Sequence; Animals; Brain-Derived Neurotrophic Factor; Calpain; Conditioning, Operant; Dipeptides; Drug Delivery Systems; Electroshock; Exploratory Behavior; Fear; Female; Fluorescence Resonance Energy Transfer; Freezing Reaction, Cataleptic; Glycoproteins; Learning Disabilities; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Confocal; Molecular Sequence Data; Nerve Tissue Proteins; Neuronal Plasticity; Peptide Fragments; Peptides; Receptors, Cholinergic; RNA Interference; RNA, Small Interfering; Single-Blind Method; Tetraethylammonium; Viral Proteins

The entorhinal cortex (EC) is one of the most vulnerable brain regions that is affected by beta amyloid (Aβ) in the early phases of Alzheimer's disease (AD). Calcium dyshomeostasis is one reason of Aβ pathology and the role of calcium channel blockers (CCBs) in this phenomenon has not fully understood. In this study, we investigated the possible neuroprotective effect of CCBs, nimodipine and isradipine against amyloid pathogenesis in EC. The Aβ 1-42 was injected bilaterally into the EC of male rats and spatial performance was assessed between 7 and 12 days after Aβ injection by Morris water maze test. Animals were daily treated by injection of various doses of nimodipine or isradipine (both at 3, 10, or 30 μg/2 μl) or their vehicles into the lateral ventricle until the start of behavioral test. Lesion in EC was assessed by measuring some proteinases involved in calcium dependent apoptotic pathway (calpain 2, caspase 12 and 3). Despite normal performance in probe test, Aβ treated rats showed delayed acquisition in a spatial reference memory task. Aβ treated rats revealed delayed acquisition in reversal memory and had deficit in probe test. The observed impairments were attenuated by isradipine (10 and 30 μg but not 3 μg) and nimodipine (30 μg). Calpain 2, caspase 12 and 3 were increased in the Aβ treated animals which was partially antagonized by isradipine and nimodipine. It is concluded that CCBs might have beneficial therapeutic effects in AD especially in the early phases of this disease.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Area Under Curve; Calcium Channel Blockers; Calpain; Caspases; Cell Death; Dose-Response Relationship, Drug; Humans; In Situ Nick-End Labeling; Isradipine; Learning Disabilities; Male; Maze Learning; Memory Disorders; Nimodipine; Peptide Fragments; Rats; Rats, Wistar; Reversal Learning; Time Factors

Early life events have profound consequences. Our research demonstrates that the early life stress of neonatal isolation (1-h individual isolation on postnatal days 2-9) in rats has immediate and enduring neural and behavioral effects. Recently, we showed neonatal isolation impaired hippocampal-dependent context conditioned fear in adult rats. We now expand upon this finding to test whether neonatal isolation impairs performance in inhibitory avoidance and in the non-aversive, hippocampal-dependent object recognition task. In addition to assessments of hippocampal-dependent memory, we examined if neonatal isolation results in cellular alterations in the adult hippocampus. This was measured with antibodies that selectively label calpain-mediated spectrin breakdown product (BDP), a marker of cytoskeletal modification that can have neuronal consequences. Neonatally isolated male and female rats showed impaired performance in both memory tasks as well as elevated BDP levels in hippocampal immunoblot samples. In tissue sections stained for BDP, the cytoskeletal fragmentation was localized to pyramidal neurons and their proximal dendrites. Interestingly, the hippocampal samples also exhibited reduced staining for the postsynaptic marker, GluR1. Neonatal isolation may render those neurons involved in memory encoding to be vulnerable to calpain deregulation and synaptic compromise as shown previously with brain injury. Together with our prior research showing enhanced striatal-dependent learning and neurochemical responsivity, these results indicate that the early experience of neonatal isolation causes enduring yet opposing region-specific neural and behavioral alterations.

Topics: Age Factors; Animals; Animals, Newborn; Calpain; Fear; Female; Hippocampus; Learning; Male; Memory Disorders; Rats; Rats, Sprague-Dawley; Recognition, Psychology; Social Isolation; Space Perception; Spectrin; Stress, Psychological

Endocannabinoids, including 2-arachidonoylglycerol and anandamide (N-arachidonoylethanolamine; AEA), have neuroprotective effects in the brain through actions at CB1 receptors. However, AEA also binds to vanilloid (VR1) receptors and induces cell death in several cell lines. Here we show that anandamide causes neuronal cell death in vitro and exacerbates cell loss caused by stretch-induced axonal injury or trophic withdrawal in rat primary neuronal cultures. Administered intracerebroventricularly, AEA causes sustained cerebral edema, as reflected by diffusion-weighted magnetic resonance imaging, regional cell loss, and impairment in long-term cognitive function. These effects are mediated, in part, through VR1 as well as through calpain-dependent mechanisms, but not through CB1 receptors or caspases. Central administration of AEA also significantly upregulates genes involved in pro-inflammatory/microglial-related responses. Thus, anandamide produces neurotoxic effects both in vitro and in vivo through multiple mechanisms independent of the CB1 receptor.

Topics: Animals; Arachidonic Acids; Calpain; Cannabinoid Receptor Modulators; Caspase 3; Caspases; Cell Death; Cells, Cultured; Cerebral Cortex; Embryo, Mammalian; Endocannabinoids; Enzyme Activation; Gene Expression Profiling; Hippocampus; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maze Learning; Memory Disorders; Mice; Neuroglia; Neurons; Polyunsaturated Alkamides; Rats

Calpains modulate processes that govern the function and metabolism of proteins key to the pathogenesis of Alzheimer's disease, including tau and amyloid precursor protein. Because activation of the calpain system might contribute to the impairment of synaptic transmission in Alzheimer's disease, we are currently testing the hypotheses that a treatment with calpain inhibitors might restore normal cognition and synaptic transmission in a transgenic model of Alzheimer's disease, the APP (K670N:M671L)/PS1(M146L) mouse. Findings derived from these studies will provide a novel approach to cognitive enhancement in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Calpain; Cysteine Proteinase Inhibitors; Disease Models, Animal; Hippocampus; Leucine; Long-Term Potentiation; Maze Learning; Membrane Proteins; Memory Disorders; Mice; Mice, Transgenic; Organ Culture Techniques; Presenilin-1; Treatment Outcome; Up-Regulation