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Biomedical subjects

Paul A Adlard

Publications and source records attributed to Paul A Adlard.

8 recordsLinked to original sources
PubMed2006

Metals and Alzheimer's disease.

There is increasing evidence to support a role for both the amyloid beta-protein precursor (AbetaPP) and its proteolytic fragment, amyloid beta (Abeta), in metal ion homeostasis. Furthermore, metal ions such as zinc and copper can interact with both AbetaPP and Abeta to potentiate Alzheimer's disease by participating in the aggregation of these normal cellular proteins and in the generation of reactive oxygen species. In addition, metal ions may interact on several other AD-related pathways, including those involved in neurofibrillary tangle formation, secretase cleavage of AbetaPP and proteolytic degradation of Abeta. As such, a dysregulation of metal ion homeostasis, as occurs with both aging and in AD, may foster an environment that can both precipitate and accelerate degenerative conditions such as AD. This offers a broad biochemical front for novel therapeutic interventions.

Aged↗
PubMed2005

Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are few therapeutics that affect the underlying disease mechanism. Recent epidemiological studies, however, suggest that lifestyle changes may slow the onset/progression of AD. Here we have used TgCRND8 mice to examine directly the interaction between exercise and the AD cascade. Five months of voluntary exercise resulted in a decrease in extracellular amyloid-beta (Abeta) plaques in the frontal cortex (38%; p = 0.018), the cortex at the level of the hippocampus (53%; p = 0.0003), and the hippocampus (40%; p = 0.06). This was associated with decreased cortical Abeta1-40 (35%; p = 0.005) and Abeta1-42 (22%; p = 0.04) (ELISA). The mechanism appears to be mediated by a change in the processing of the amyloid precursor protein (APP) after short-term exercise, because 1 month of activity decreased the proteolytic fragments of APP [for alpha-C-terminal fragment (alpha-CTF), 54% and p = 0.04; for beta-CTF, 35% and p = 0.03]. This effect was independent of mRNA/protein changes in neprilysin and insulin-degrading enzyme and, instead, may involve neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise. Long-term exercise also enhanced the rate of learning of TgCRND8 animals in the Morris water maze, with significant (p < 0.02) reductions in escape latencies over the first 3 (of 6) trial days. In support of existing epidemiological studies, this investigation demonstrates that exercise is a simple behavioral intervention sufficient to inhibit the normal progression of AD-like neuropathology in the TgCRND8 mouse model.

Alzheimer Disease↗
PubMed2005

The exercise-induced expression of BDNF within the hippocampus varies across life-span.

Voluntary exercise increases hippocampal brain-derived neurotrophic factor (BDNF) expression in young animals. In this investigation we examined the induction of BDNF protein in the hippocampus of young (2 months), late middle-aged (15 months) and old (24 months) animals over 4 weeks of exercise. Average running distances decreased with age, with the old animals also maintaining a constant level of activity over time, whereas the other groups tended to increase their average running distance. All animals demonstrated a biphasic profile of BDNF protein induction, with a significant (P<0.05) increase after 1 week of exercise followed by a decrease to near sedentary levels at 2 weeks. After this, BDNF protein levels increased significantly (P<0.05), as compared to baseline, primarily only in the young animals. In whole hippocampal homogenates, only particular BDNF mRNA exons were significantly (P<0.05) changed as a result of exercise, with the largest induction occurring in young animals. BDNF protein induction may, therefore, not be directly correlated with significant mRNA changes. Exercise may represent a therapeutic tool for disorders which involve a decrease in BDNF.

Age Factors↗
PubMed2005

Exercise-induced gene expression changes in the rat spinal cord.

There is growing evidence that exercise benefits recovery of neuromuscular function from spinal cord injury (SCI). However, the effect of exercise on gene expression in the spinal cord is poorly understood. We used oligonucleotide microarrays to compare thoracic and lumbar regions of spinal cord of either exercising (voluntary wheel running for 21 days) or sedentary rats. The expression data were filtered using statistical tests for significance, and K-means clustering was then used to segregate lists of significantly changed genes into sets based upon expression patterns across all experimental groups. Levels of brain-derived neurotrophic factor (BDNF) protein were also measured after voluntary exercise, across different regions of the spinal cord. BDNF mRNA increased with voluntary exercise, as has been previously shown for other forms of exercise, contributed to by increases in both exon I and exon III. The exercise-induced gene expression changes identified by microarray analysis are consistent with increases in pathways promoting neuronal health, signaling, remodeling, cellular transport, and development of oligodendrocytes. Taken together these data suggest cellular pathways through which exercise may promote recovery in the SCI population.

Animals↗
PubMed2004

The timecourse of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exercise.

In this study we examined the timecourse of induction of brain-derived neurotrophic factor (BDNF) mRNA and protein after 1, 3, 5, 7, 14 and 28 days of exercise in the rat. To measure the expression of mRNA for individual BDNF exons we utilized a semi-quantitative RT-PCR technique, while BDNF protein was assessed using commercial ELISA kits. We demonstrated that the distance run by animals increased significantly (P<0.05) after 4 weeks. BDNF protein was significantly (P<0.05) increased after 4 weeks of exercise, while the mRNA for individual BDNF exons increased significantly (P<0.05) over the timecourse (exon I after 1 and 28 days and exons II and V after 28 days). The Morris water maze was then utilized to demonstrate that 3 weeks of prior exercise enhanced the rate of learning on this task. Exercise, therefore, was shown to modulate BDNF induction in a time-dependent manner, and this may translate to improvements in neurotrophin-mediated tasks within the CNS.

Analysis of Variance↗
PubMed2004

Neuron-glia communication: metallothionein expression is specifically up-regulated by astrocytes in response to neuronal injury.

Recent data suggests that metallothioneins (MTs) are major neuroprotective proteins within the CNS. In this regard, we have recently demonstrated that MT-IIA (the major human MT-I/-II isoform) promotes neural recovery following focal cortical brain injury. To further investigate the role of MTs in cortical brain injury, MT-I/-II expression was examined in several different experimental models of cortical neuron injury. While MT-I/-II immunoreactivity was not detectable in the uninjured rat neocortex, by 4 days, following a focal cortical brain injury, MT-I/-II was found in astrocytes aligned along the injury site. At latter time points, astrocytes, at a distance up to several hundred microns from the original injury tract, were MT-I/-II immunoreactive. Induced MT-I/-II was found both within the cell body and processes. Using a cortical neuron/astrocyte co-culture model, we observed a similar MT-I/-II response following in vitro injury. Intriguingly, scratch wound injury in pure astrocyte cultures resulted in no change in MT-I/-II expression. This suggests that MT induction was specifically elicited by neuronal injury. Based upon recent reports indicating that MT-I/-II are major neuroprotective proteins within the brain, our results provide further evidence that MT-I/-II plays an important role in the cellular response to neuronal injury.

Animals↗
PubMed2001

Morphologically distinct plaque types differentially affect dendritic structure and organisation in the early and late stages of Alzheimer's disease.

We have investigated the effects of the deposition of insoluble beta-amyloid plaques on dendritic morphology within the neocortex. Labelling for beta-amyloid identified three morphologically distinct plaque types present both within the brains of preclinical Alzheimer's disease (AD) and end-stage AD cases. In both preclinical and end-stage AD, the percentage area occupied by diffuse plaques contained a greater density of labelling for microtubule-associated protein-2 (MAP2) relative to the surrounding neuropil (case type, ratio of MAP2 labelling in plaque to MAP2 labelling in surrounding neuropil +/- SEM: preclinical, 1.27+/-0.04; end-stage, 1.32+/-0.05). In contrast, there was a greater density of MAP2-labelled processes surrounding dense-cored plaques compared to that found within the plaque area (preclinical, 0.73+/-0.05; end-stage, 0.62+/-0.07). Fibrillar plaques demonstrated a transition from the early to late stages of AD, with a substantial decrease in the density of MAP2 labelling within the plaque area in end-stage AD cases relative to preclinical AD cases (preclinical, 1.01+/-0.1; end-stage, 0.72+/-0.05). The morphology of dendrites associated with dense-core or fibrillar plaques suggest physical disruption of the neuropil by beta-amyloid plaque formation. These data demonstrate that plaque isoforms differentially affect dendritic morphology in both the early and late stages of AD, with progression to clinical AD associated with evolving dendritic damage localised to fibrillar and dense-core plaques.

Aged↗