Biomedical subjects

Carl W Cotman

Publications and source records attributed to Carl W Cotman.

At least 19 recordsLinked to original sources

PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Spatial patterns of mammalian brain aging: distribution of cathepsin D-immunoreactive cell bodies and dystrophic dendrites in aging dogs resembles that in Alzheimer's disease.

Elevated levels of the lysosomal enzyme cathepsin D are found in the early stages of Alzheimer's disease (AD) and co-occur with intraneuronal tangles. The present study tested whether increases in cathepsin D would emerge during aging in another mammalian species. Regional brain patterns of cathepsin D immunostaining were compared in dogs ages 0.35 to 16 years. Accumulations of immunopositive material were evident in neuronal cell bodies in many forebrain sites in middle-age to old dogs (>/=6 years). Three types could be distinguished: (1) dense aggregates with no particular position within the cell body; (2) crescent-shaped "caps" that occupied one pole of the cell body; and (3) very dense "spikes" that extended from the cell body for variable distances into the apical dendrite; these spikes were found in only a few areas, most notably the subiculum and layer V of neocortex. The spikes appeared between ages 2 and 5 years and increased steadily with age thereafter. Spikes were found in the subiculum in the aged human brain but only infrequently; they were, however, present in large numbers in AD brains. These results established that brain aging in dogs is (1) well advanced by middle age, (2) varies markedly across regions, and (3) in at least some of its aspects (dystrophic dendrites) is prominent in areas known to exhibit pathology early in the course of AD. Combined with previous results for rats, these findings indicated that changes in cathepsin D observed in AD, in particular in the temporal lobe, reflect a generalized mammalian pattern of brain aging.

Aged↗

PubMed2003

Exercise increases the vulnerability of rat hippocampal neurons to kainate lesion.

Available evidence suggests that regular, moderate-intensity exercise has beneficial effects on neural health, perhaps including neuroprotection. To evaluate this idea further, we compared the severity of kainate-induced neuronal loss in exercised versus sedentary female rats. Stereological estimations of neuron number revealed that rats in the exercise condition exhibited significantly greater neuron loss in hippocampal region CA2/3, suggesting that high levels of physical activity may increase neuronal vulnerability to excitotoxicity.

Animals↗

PubMed2003

Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.

Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.

Aged↗

PubMed2003

Fas and Fas ligand are associated with neuritic degeneration in the AD brain and participate in beta-amyloid-induced neuronal death.

It has recently been suggested that neuronal cell death in response to many brain insults may be mediated by the upregulation of tumor necrosis factor receptor (TNFR) family members and their ligands. In the present study, we investigated whether the expression of the TNFR family death domain receptor, Fas, and its ligand, FasL, is altered in association with neuropathology and activated caspase markers in Alzheimer disease (AD) brain, and Abeta-induced neuronal cell death in vitro. To evaluate this hypothesis, we examined Fas and FasL expression in AD and control brain, and Abeta-treated primary neurons, using immunocytochemistry and Western blots. Neurons in both AD brain and Abeta-treated cultures exhibited FasL upregulation and changes in immunoreactivity for Fas receptor. Further, FasL expression was remarkably elevated in senile plaques and neurofilament-positive dystrophic neurites, and in association with caspase activation and neuritic apoptosis in AD brain. Based on these and previous data regarding protection of primary neuronal cultures from Abeta(1-42)-induced apoptosis by blockade of Fas-associated death domain signaling, we also tested the hypothesis that dynamic regulation of Fas and FasL may contribute to Abeta-mediated neuronal cell death. Accordingly, neuronal cultures derived from mice carrying inactivating mutations in Fas (Faslpr) or FasL (Fasgld) exhibited protection from Abeta(1-42)-induced cell death. These findings suggest that Fas-FasL interactions may contribute to mechanisms of neuronal loss and neuritic degeneration in AD.

Aged↗

PubMed2003

The induction of the TNFalpha death domain signaling pathway in Alzheimer's disease brain.

The tumor necrosis factor-alpha death domain pathway contributes to cellular degeneration in a variety of conditions. This study investigates the hypothesis that this death domain pathway is progressively induced in the brain during the progression of Alzheimer's disease (AD). AD cases had increased levels of proapoptotic markers including tumor necrosis factor-alpha (TNFalpha), TNF receptor type 1 (TNF-R1), TNF receptor-associated death domain (TRADD), and caspase-3, 2- to 10-fold higher (P < .01) than age-matched controls and 1 to 3 times higher than transitional cases. In striking contrast, potentially neuroprotective TNF receptor type 2 (TNF-R2), and Fas-associated death domain-like interleukin-1beta-converting enzyme (FLICE) inhibitor protein (FLIP) were decreased in AD as compared with age-matched control cases (P < .01). Overall, there was an elevation in proapoptotic elements, including a 5-fold increase in TNF-R1 and a 12-fold decrease in FLIP in AD brains. These changes may translate to increased degenerative potential because the downstream effector caspase-3 and product of the TNF pathway was also increased in parallel with enhanced TNF proapoptotic conditions. Our findings suggest that the TNF death receptor pathway and caspases are activated in the early stages of neuronal degeneration in AD.

Alzheimer Disease↗

PubMed2003

Locomotor activity rhythms in dogs vary with age and cognitive status.

Beagle dogs exhibited diurnal patterns of locomotor activity that varied as a function of age, cognitive status, and housing environment. Aged dogs housed in an indoor facility showed a delayed onset of activity following lights on and displayed shorter bouts of activity, with more rest periods during the day, compared with young dogs. Cognitively impaired aged dogs were more active and showed a delayed peak of activity compared with unimpaired aged dogs. Housing in continuous light did not disrupt activity rhythms. The effect of age was less prominent in dogs housed in an indoor/outdoor facility. This suggests that bright sunlight and natural light-dark transitions are better able to consolidate and synchronize the activity rhythms of the dogs.

Aging↗

PubMed2003

Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid.

The role of adjuvant on the T(h)1 and T(h)2 immune responses to Abeta-immunotherapy (Abeta(42 )peptide) was examined in wild-type mice. Fine epitope analysis with overlapping oligomers of the Abeta(42) sequence identified the 1-15 region as a dominant B cell epitope. The 6-20 peptide was recognized only weakly by antisera from mice administrated with Abeta(42) peptide formulated in complete Freund's adjuvant (CFA), alum or TiterMax Gold (TMG). However, mice immunized with Abeta(42) mixed with QS21 induced a significant antibody response to the 6-20 peptide. The only T cell epitope found was within the 6-28 sequence of Abeta(42). QS21 and CFA induced the strongest humoral response to Abeta, alum was intermediate, and TMG the weakest adjuvant. Analysis of antibody isotypes specific for Abeta indicates that alum induces primarily T(h)2-type immune response, whereas TMG, CFA and QS21 shift the immune responses toward a T(h)1 phenotype. Stimulation of splenocytes from Abeta-immunized mice with Abeta(40) peptide induced strikingly different cytokine expression profiles. QS21 and CFA induced significant IFN-gamma, IL-4 and tumor necrosis factor-alpha expression, whereas alum induced primarily IL-4 production. As T(h)1-type immune responses have been implicated in many autoimmune disorders, whereas T(h)2-type responses have been shown to inhibit autoimmune disease, the choice of adjuvant may be critical for the design of a safe and effective immunotherapy for Alzheimer's disease.

Adjuvants, Immunologic↗

PubMed2002

Beta-amyloid deposition and neurofibrillary tangle association with caspase activation in Down syndrome.

Individuals with Down syndrome (DS) and Alzheimer's disease (AD) develop senile plaques, neurofibrillary tangles (NFT), and neuron loss. Recent studies demonstrate the activation of apoptotic pathways in AD; less data is available in DS. The DS brain was examined using immunocytochemistry and antibodies against the active fragment of caspase-8 (AC, 8) and to caspase-3 cleavage products of fodrin (CCP), a neuronal cytoskeleton protein. The hippocampus demonstrated widespread accumulation of fodrin CCP and AC8 in NFTs and dystrophic neurites. Individual neurons contained intracellular beta-amyloid (Abeta) and fodrin CCP providing evidence that caspase activation can occur with both NFT and Abeta. Abeta within or around neurons in addition to contributing to NFT formation may also trigger apoptotic pathways. Caspase activation may lead to the cleavage of critical cellular proteins and neuronal cell death associated with DS.

Adult↗

PubMed2002

Hippocampal brain-derived neurotrophic factor gene regulation by exercise and the medial septum.

Brain-derived neurotrophic factor (BDNF) enhances synaptic plasticity and neuron function. We have reported that voluntary exercise increases BDNF mRNA levels in the hippocampus; however, mechanisms underlying this regulation have not been defined. We hypothesized that medial septal cholinergic and/or gamma amino butyric acid (GABA)ergic neurons, which provide a major input to the hippocampus, may regulate the baseline gene expression and exercise-dependent gene upregulation of this neurotrophin. Focal lesions were produced by medial septal infusion of the saporin-linked immunotoxins 192-IgG-saporin or OX7-saporin. 192-IgG-saporin produced a selective and complete loss of medial septal cholinergic neurons with no accompanying GABA loss. Baseline BDNF mRNA was reduced in the hippocampus of sedentary animals, but exercise-induced gene upregulation was not impaired, despite complete loss of septo-hippocampal cholinergic afferents. OX7-saporin produced a graded lesion of the medial septum characterized by predominant GABA neuron loss with less reduction in the number of cholinergic cells. OX7-saporin lesion reduced baseline hippocampal BDNF mRNA and attenuated exercise-induced gene upregulation, in a dose-dependent manner. These results suggest that combined loss of septal GABAergic and cholinergic input to the hippocampus may be important for exercise-dependent BDNF gene regulation, while cholinergic activity on its own is not sufficient. These results are discussed in relation to their implications for aging and Alzheimer's disease.

Acetylcholine↗

PubMed2002

Caspase-cleaved amyloid precursor protein and activated caspase-3 are co-localized in the granules of granulovacuolar degeneration in Alzheimer's disease and Down's syndrome brain.

Granulovacuolar degeneration (GVD) is a diagnostic neuropathological feature of Alzheimer's disease (AD). In some neurons, apoptosis has been hypothesized to be a primary mechanism causing neuronal cell death in AD. In this study we investigated CA1 neurons with GVD in AD and Down's syndrome (DS) brain. We demonstrated that activated caspase-3 and a caspase-cleaved cleavage product of the amyloid precursor protein (cAPP) are co-localized in GVD granules, and that these same cells often show nuclear DNA damage. In contrast, activated caspase-8 is present in the cytoplasm but not within the granules of GVD neurons. A caspase-cleavage product of fodrin that accumulates in many AD and DS neurons is not present in GVD granules. These data support a role for the activation of apoptotic mechanisms in selective compartments exhibiting GVD.

Aged↗

PubMed2002

Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid.

Accumulation of oxidative damage to mitochondria, protein, and nucleic acid in the brain may lead to neuronal and cognitive dysfunction. The effects on cognitive function, brain mitochondrial structure, and biomarkers of oxidative damage were studied after feeding old rats two mitochondrial metabolites, acetyl-l-carnitine (ALCAR) [0.5% or 0.2% (wt/vol) in drinking water], and/or R-alpha-lipoic acid (LA) [0.2% or 0.1% (wt/wt) in diet]. Spatial memory was assessed by using the Morris water maze; temporal memory was tested by using the peak procedure (a time-discrimination procedure). Dietary supplementation with ALCAR and/or LA improved memory, the combination being the most effective for two different tests of spatial memory (P < 0.05; P < 0.01) and for temporal memory (P < 0.05). Immunohistochemical analysis showed that oxidative damage to nucleic acids (8-hydroxyguanosine and 8-hydroxy-2'-deoxyguanosine) increased with age in the hippocampus, a region important for memory. Oxidative damage to nucleic acids occurred predominantly in RNA. Dietary administration of ALCAR and/or LA significantly reduced the extent of oxidized RNA, the combination being the most effective. Electron microscopic studies in the hippocampus showed that ALCAR and/or LA reversed age-associated mitochondrial structural decay. These results suggest that feeding ALCAR and LA to old rats improves performance on memory tasks by lowering oxidative damage and improving mitochondrial function.

Acetylcarnitine↗

PubMed2002

Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia.

BACKGROUND: The neurotransmitters dopamine and glutamate have been implicated in the prefrontal dysfunction associated with schizophrenic illness. Studies suggest that the D1 subclass of dopamine receptor and the N-methyl-D-aspartate subclass of glutamate receptor are involved in this prefrontal dysfunction. These 2 receptors regulate, in opposing directions, the amount of phosphorylated activated DARPP-32, a potent inhibitor of protein phosphatase 1 that modulates the activity of several classes of receptors and ion channels. Thus, DARPP-32 occupies a key regulatory position, and may play an important role in the pathophysiological changes in dopamine and glutamate function reported in patients with schizophrenia. METHODS: The amounts of DARPP-32, synapsin I, and the alpha subunit of calcium/calmodulin-dependent protein kinase II were measured by immunoblotting in postmortem samples from 14 schizophrenic subjects and their age-, gender-, and autolysis time-matched control subjects. Possible confounding influences of neuroleptic treatment were analyzed by comparing subjects with Alzheimer disease who were and were not treated with neuroleptic agents. RESULTS: DARPP-32 was significantly reduced in the dorsolateral prefrontal cortex in more schizophrenic subjects relative to matched controls. The ratios of 2 other synaptic phosphoproteins, synapsin I and the alpha subunit of calcium/calmodulin-dependent protein kinase II, did not differ between schizophrenic and control subjects, nor between subjects with Alzheimer disease who were and were not treated with neuroleptic agents. CONCLUSIONS: Our findings are consistent with a selective reduction in DARPP-32 levels in schizophrenic subjects. This may be involved in the prefrontal dysfunction associated with schizophrenia.

Adult↗

PubMed2002

Caspase-9 activation and caspase cleavage of tau in the Alzheimer's disease brain.

Accumulating evidence supports a role for the activation of proteolytic enzymes, caspases, in the Alzheimer's disease (AD) brain. Neurons committed to apoptosis may do so through a mitochondrial pathway employing caspase-9 or through an alternative, receptor-mediated pathway involving caspase-8. Considering the role of mitochondrial dysfunction in AD, we examined the possible activation of caspase-9 in the AD brain using an antibody that recognizes the active fragments of caspase-9, but not the full-length proform of the enzyme. In vivo immunohistochemical analysis demonstrated little caspase-9 activation in the majority of hippocampal brain sections from control brains. However, labeling of neurons as well as dystrophic neurites within plaque regions was observed in all AD hippocampal brain sections examined. In addition, active caspase-9 was colocalized with active caspase-8 and the accumulation of caspase-3-cleavage products of fodrin. The activation of caspase-9 was also observed in neurons positive for oxidative damage to DNA/RNA. A quantitative analysis indicates that as the number of neurons containing neurofibrillary tangles (NFTs) increases, the extent of caspase-9 activation decreases, supporting the idea that caspase-9 activation may precede NFT formation. In addition, a site-directed caspase-cleavage antibody was designed to the amino-terminal caspase-3 consensus cleavage site located in tau, and shown to be an effective marker for caspase-cleaved fragments of tau in vitro. Analysis with this antibody using age-matched control or AD brain sections demonstrated no staining in control brains while widespread labeling of NFTs, neuropil threads, and dystrophic neurites was observed in AD sections. Taken together, these results demonstrate the activation of caspases and cleavage of tau in the AD brain, events which may precede and lead to the formation of NFTs.

Aged↗

PubMed2002

Exercise: a behavioral intervention to enhance brain health and plasticity.

Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life. Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.

Acetylcholine↗

PubMed2002

Exercise enhances and protects brain function.

Physical activity, in the form of voluntary wheel running, induces gene expression changes in the brain. Animals that exercise show an increase in brain-derived neurotrophic factor, a molecule that increases neuronal survival, enhances learning, and protects against cognitive decline. Microarray analysis of gene expression provides further support that exercise enhances and supports brain function.

Animals↗

PubMed2002

Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice.

We have studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD brain biopsy, human short postmortem brain tissues, and yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (AbetaPP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild type, 5 kb deleted, and mouse mtDNA was performed, along with immunocytochemistry using antibodies against amyloid precursor protein (APP), 8-hydroxy-2'-guanosine (8-OHG), and cytochrome c oxidase (COX). There was a higher degree of amyloid deposition in the vascular walls of the human AD, YAC, and C57B6/SJL Tg (+) mice compared to age-matched controls. In addition, vessels with more severe lesions showed immunopositive staining for APP and possessed large, lipid-laden vacuoles in the cytoplasm of endothelial cells (EC). Significantly more mitochondrial abnormalities were seen in human AD, YAC, and C57B6/SJL Tg (+) mouse microvessels where lesions occurred. In situ hybridization using wild and chimera (5 kb) mtDNA probes revealed positive signals in damaged mitochondria from the vascular endothelium and in perivascular cells of lesioned microvessels close to regions of large amyloid deposition. These features were absent in undamaged regions of human AD tissues, YAC and C57B6/SJL Tg (+) mouse tissues, and in age-matched control subjects. In addition, vessels with atherosclerotic lesions revealed endothelium and perivascular cells possessing clusters of wild and deleted mtDNA positive probes. These mtDNA deletions were accompanied by increased amounts of immunoreactive APP, 8-OHG, and COX in the same cellular compartment. Our observations demonstrate that vascular wall cells, especially their mitochondria, appear to be a central target for oxidative stress-induced damage.

Alzheimer Disease↗

PubMed2002

Achieving and maintaining cognitive vitality with aging.

Cognitive vitality is essential to quality of life and survival in old age. With normal aging, cognitive changes such as slowed speed of processing are common, but there is substantial interindividual variability, and cognitive decline is clearly not inevitable. In this review, we focus on recent research investigating the association of various lifestyle factors and medical comorbidities with cognitive aging. Most of these factors are potentially modifiable or manageable, and some are protective. For example, animal and human studies suggest that lifelong learning, mental and physical exercise, continuing social engagement, stress reduction, and proper nutrition may be important factors in promoting cognitive vitality in aging. Manageable medical comorbidities, such as diabetes, hypertension, and hyperlipidemia, also contribute to cognitive decline in older persons. Other comorbidities such as smoking and excess alcohol intake may contribute to cognitive decline, and avoiding these activities may promote cognitive vitality in aging. Various therapeutics, including cognitive enhancers and protective agents such as antioxidants and anti-inflammatories, may eventually prove useful as adjuncts for the prevention and treatment of cognitive decline with aging. The data presented in this review should interest physicians who provide preventive care management to middle-aged and older individuals who seek to maintain cognitive vitality with aging.

Aging↗