calpain and Cognition-Disorders

Cognitive impairment, significantly reducing processing speed and executive function, is the critical consequence of cerebral small vessel disease (SVD), in which genetic variations have been studied. In this study, we explore the role of SNP43 (G/A) and SNP63 (C/T) polymorphism in the CAPN10 on cognitive impairment process in cerebral SVD.. Cerebral SVD patients (n = 224) and healthy controls (n = 187) were recruited. The relationship between frequency distribution of SNP43 (G/A) and SNP63 (T/C) genotype and allele in CAPN10 gene, and cognitive impairment was examined. The independent risk factors for cognitive impairment in SVD were determined by logistic regression analysis.. Accordingly, the frequency distribution of genotype and allele at SNP43 (G/A) was significantly different between cerebral SVD patients and healthy controls. Cerebral SVD patients with GG genotype were more susceptible for cognitive impairment, whereas cerebral SVD patients with GA + AA genotype were less possible to suffer from cognitive impairment, compared with those with GG genotype. And also, cerebral SVD does not include SNP63 (C/T) to associate with cognitive impairment, and SNP43 (G/A), total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein were independent risk factors for cognitive impairment in SVD.. Our study provides evidence that SNP43 (G/A) in the CAPN10 gene increases the risk of cognitive impairment in SVD patients. Besides it is proven that, patients with G allele are more susceptible to suffer from cerebral SVD with worse cognitive impairment.

Topics: Aged; Blood Pressure; Calpain; Cerebral Small Vessel Diseases; Cognition Disorders; Female; Genotype; Humans; Logistic Models; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Polymorphism, Single Nucleotide; Retrospective Studies; Risk Factors

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

The senescence-accelerated mouse-prone 8 (SAMP8), used as a model of aging, displays many established pathological features of Alzheimer's disease. Cognitive impairments and increased levels of hyperphosphorylated tau are found in the hippocampus of SAMP8 mice along with an increased β-secretase activity and amyloid-β (Aβ) depositions that increase in number and extent with age. Based on a previous study from our laboratory showing an amelioration of cognitive impairments and tau pathology by sildenafil, in this study we tested whether this drug could also modulate the amyloid precursor protein amyloidogenic processing in this mouse model. Our results show that the protein levels of the β-secretases β-site amyloid precursor protein cleaving enzyme 1 and cathepsin B are higher in the hippocampus of 9-month-old SAMP8 mice than those of age-matched senescence-resistant-1. Sildenafil (7.5mg/kg for 4 weeks) attenuated learning and memory impairments shown by SAMP8 mice in the passive avoidance test. The increased expression of β-site amyloid precursor protein cleaving enzyme 1 was also reduced by sildenafil, an effect paralleled to decreases in the activities of two β-site amyloid precursor protein cleaving enzyme 1 modulators, calpain and cyclin-dependent kinase 5 protein. Interestingly, sildenafil enhanced both Akt and glycogen synthase kinase-3β (ser9) phosphorylation, which could be mediating the reduction in cathepsin B levels found in the hippocampus of sildenafil-treated SAMP8 mice. Sildenafil-induced reduction in β-site amyloid precursor protein cleaving enzyme 1 and cathepsin B expression in SAMP8 mice was associated with a decrease in hippocampal Aβ42 levels which, in turn, could mediate the parallel decline in glial fibrillary acidic protein expression observed in these animals. These findings highlight the therapeutic potential of sildenafil in Alzheimer's disease pathogenesis.

Topics: Aging; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Calpain; Cathepsin B; Cognition Disorders; Cyclin-Dependent Kinase 5; Glial Fibrillary Acidic Protein; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Hippocampus; Mice; Models, Animal; Phosphodiesterase 5 Inhibitors; Phosphorylation; Piperazines; Proto-Oncogene Proteins c-akt; Purines; RNA, Messenger; Sildenafil Citrate; Sulfonamides

Epidemiological study reveals that socially isolated persons have increased risk of developing Alzheimer's disease (AD). Whether this risk arises from an oxidative stress is unclear. Here we show that N-acetylcysteine (NAC), an anti-oxidant, is capable of preventing social isolation-induced accelerated impairment of contextual fear memory and rundown of hippocampal LTP in 3-month old APP/PS1 mice. Increased hippocampal levels of γ-secretase activity, Aβ-40 and Aβ-42 seen in the isolated APP/PS1 mice were reduced by chronic treatment of NAC. In addition, social isolation-induced increase in calpain activity and p25/p35 ratio concomitant with decrease in membrane-associated p35 and p35/Cdk5 activity was normalized by NAC. NAC pretreatment also reversed isolation-induced decrease in GluR1 Ser831 phosphorylation, surface expression of AMPARs and p35-GluR1-CaMKII interactions. These results suggest that NAC decreases γ-secretase activity resulting in the attenuation of Aβ production, calpain activity and conversion of p35 to p25 which stabilized p35-GluR1-CaMKII interactions and restored GluR1 and GluR2 surface expression. Our results indicate that NAC is effective in mouse models of AD and has translation potential for the human disorder.

Topics: Acetylcysteine; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Antioxidants; Biophysics; Biotinylation; Calpain; Cell Line, Transformed; Cognition Disorders; Conditioning, Psychological; Cyclin-Dependent Kinase 5; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Enzyme-Linked Immunosorbent Assay; Fear; Hippocampus; Humans; In Vitro Techniques; Long-Term Potentiation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Patch-Clamp Techniques; Peptide Fragments; Presenilin-1; Protein Kinase C-delta; Receptors, Metabotropic Glutamate; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Social Isolation; Time Factors; Transfection

Recent reports demonstrate that the activation and interaction of the protease calpain (CP) and the protein phosphatase calcineurin (CN) are elevated in the late stages of Alzheimer's disease (AD). However, the extent to which CPs and CN interact during earlier stages of disease progression remains unknown. Here, we investigated CP and CN protein levels in cytosolic, nuclear, and membrane fractions prepared from human postmortem hippocampal tissue from aged non-demented subjects, and subjects diagnosed with mild cognitive impairment (MCI). The results revealed a parallel increase in CP I and the 48 kDa CN-Aα (ΔCN-Aα48) proteolytic fragment in cytosolic fractions during MCI. In primary rat hippocampal cultures, CP-dependent proteolysis and activation of CN was stimulated by application of oligomeric Aβ((1-42)) peptides. Deleterious effects of Aβ on neuronal morphology were reduced by blockade of either CP or CN. NMDA-type glutamate receptors, which help regulate cognition and neuronal viability, and are modulated by CPs and CN, were also investigated in human hippocampus. Relative to controls, MCI subjects showed significantly greater proteolytic levels of the NR2B subunit. Within subjects, the extent of NR2B proteolysis was strongly correlated with the generation of ΔCN-Aα48 in the cytosol. A similar proteolytic pattern for NR2B was also observed in primary rat hippocampal cultures treated with oligomeric Aβ and prevented by inhibition of CP or CN. Together, the results demonstrate that the activation and interaction of CPs and CN are increased early in cognitive decline associated with AD and may help drive other pathologic processes during disease progression.

Topics: Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Calcineurin; Calcineurin Inhibitors; Calcium; Calpain; Case-Control Studies; Cell Culture Techniques; Cell Fractionation; Cognition Disorders; Disease Progression; Enzyme Activation; Enzyme Inhibitors; Female; Glutamic Acid; Hippocampus; Humans; Male; Peptide Fragments; Rats; Receptors, N-Methyl-D-Aspartate; Retrospective Studies; Signal Transduction

Marked increases in intracellular calcium may play a role in mediating cellular dysfunction and death following central nervous system trauma, in part through the activation of the calcium-dependent neutral protease calpain. In this study, we evaluated the effect of the calpain inhibitor AK295 [Z-Leu-aminobutyric acid-CONH(CH2)3-morpholine] on cognitive and motor deficits following lateral fluid percussion brain injury in rats. Before injury, male Sprague-Dawley rats (350-425 g) were trained to perform a beam-walking task and to learn a cognitive test using a Morris water maze paradigm. Animals were subjected to fluid percussion injury (2.2-2.4 atm; 1 atm = 101.3 kPa) and, beginning at 15 min postinjury, received a continuous intraarterial infusion of AK295 (120-140 mg/kg, n = 15) or vehicle (n= 16) for 48 hr. Sham (uninjured) animals received either drug (n = 5) or vehicle (n = 10). Animals were evaluated for neurobehavioral motor function at 48 hr and 7 days postinjury and were tested in the Morris water maze to evaluate memory retention at 7 days postinjury. At 48 hr, both vehicle- and AK295-treated injured animals showed significant neuromotor deficits (P< 0.005). At 7 days, injured animals that received vehicle continued to exhibit significant motor dysfunction (P< 0.01). However, brain-injured, AK295-treated animals showed markedly improved motor scores (P<0.02), which were not significantly different from sham (uninjured) animals. Vehicle-treated, injured animals demonstrated a profound cognitive deficit (P< 0.001), which was significantly attenuated by AK295 treatment (P< 0.05). To our knowledge, this study is the first to use a calpain inhibitor following brain trauma and suggests that calpain plays a role in the posttraumatic events underlying memory and neuromotor dysfunction.

Topics: Animals; Brain Injuries; Calpain; Cognition Disorders; Cysteine Proteinase Inhibitors; Dipeptides; Disease Models, Animal; Male; Memory; Psychomotor Performance; Rats; Rats, Sprague-Dawley