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Biomedical subjects

David S Albers

Publications and source records attributed to David S Albers.

9 recordsLinked to original sources
PubMed2004

Elevated levels of matrix metalloproteinases-9 and -1 and of tissue inhibitors of MMPs, TIMP-1 and TIMP-2 in postmortem brain tissue of progressive supranuclear palsy.

We determined the levels and tissue localization of matrix metalloproteinases (MMPs) as well as their endogenous tissue inhibitors (TIMPs) in postmortem brain tissue from 13 patients with progressive supranuclear palsy (PSP) and 8 age-matched controls. MMP-9 expression was significantly increased in both the frontal cortex (p = 0.002) and substantia nigra (p = 0.003) of PSP cases as compared to controls whereas MMP-1 levels were increased in the substantia nigra (p = 0.01) but unchanged in the frontal cortex (p = 0.41). Levels of the endogenous tissue inhibitors of MMPs, TIMP-1 and TIMP-2 were significantly elevated in the substantia nigra (TIMP-1: p = 0.004, TIMP-2: p = 0.01). Levels of TIMPs were unchanged in PSP frontal cortex as compared to control cases. Together, these data show alterations of MMPs and TIMPs in the substantia nigra as well as in the frontal cortex of PSP, consistent with the possibility that alterations in MMPs/TIMPs may contribute to disease pathogenesis.

Aged↗
PubMed2003

Minocycline enhances MPTP toxicity to dopaminergic neurons.

Minocycline has been shown previously to have beneficial effects against ischemia in rats as well as neuroprotective properties against excitotoxic damage in vitro, nigral cell loss via 6-hydroxydopamine, and to prolong the life-span of transgenic mouse models of Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). We investigated whether minocycline would protect against toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that selectively destroys nigrostriatal dopaminergic (DA) neurons and produces a clinical state similar to Parkinson's disease (PD) in rodents and primates. We found that although minocycline inhibited microglial activation, it significantly exacerbated MPTP-induced damage to DA neurons. We present evidence suggesting that this effect may be due to inhibition of DA and 1-methyl-4-phenylpridium (MPP+) uptake into striatal vesicles.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

Age-related microglial activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in C57BL/6 mice.

Microglial activation was investigated in the brains of young (3 months old) and older (9-12 months old) mice following administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tyrosine hydroxylase (TH)-positive neuronal loss differed significantly between young and older mice. Importantly, the two groups clearly demonstrated a distinct microglial activation pattern. In young mice which showed TH neuronal loss at 1 day (33.4%), 3 days (45.1%), 7 days (47.1%) and 14 days (46.9%), microglial activation was first observed at 1 day, with lesser activation at 3 days and none shown later than 7 days. In contrast, in older mice which showed TH neuronal loss at 1 day (49.6%), 3 days (56.1%), 7 days (71.7%) and 14 days (72.1%), microglial activation occurred at 1 day, further intensified at 3-7 days, and was largely abated by 14 days. The double immunohistochemistry further demonstrated that the activated microglia surrounded dopaminergic neurons in older mice at 7 days, which was sharply in contrast to the young mice which were devoid of massive microglial activation in the SN later than 3 days after MPTP treatment. The present study suggests that age-related microglial activation in the SN may be relevant to the higher susceptibility to MPTP neurotoxicity in older mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer's disease.

Matrix metalloproteinases (MMPs) may play a role in the pathophysiology of Alzheimer's disease (AD). MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) are elevated in postmortem brain tissue of AD patients. MMPs and TIMPs are found in neurons, microglia, vascular endothelial cells and leukocytes. The aim of this study was to determine whether circulating levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 are elevated in the plasma of AD patients. We compared AD patients to age- and gender-matched controls as well as to Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) patients. There was constitutive expression of gelatinase A (MMP-2), and gelatinase B (MMP-9), in all the samples as shown by zymographic analysis. Levels of MMP-9 were significantly (P=0.003) elevated in the plasma of AD patients as compared to controls. Plasma levels of MMP-2, TIMP-1 and TIMP-2 were unchanged. There were no significant changes of MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in PD and ALS samples. TIMP-1 and TIMP-2 were significantly correlated with MMP-9 in the AD patients. ApoE genotyping of plasma samples showed that levels of MMP-2, TIMP-1 and TIMP-2 and MMP-9 were not significantly different between the ApoE subgroups. These findings indicate that circulating levels of MMP-9 are increased in AD and may contribute to disease pathology.

Aged↗
PubMed2002

Stress-induced mitochondrial depolarization and oxidative damage in PSP cybrids.

Increased oxidative damage and mitochondrial dysfunction have been suggested to play critical roles in the pathogenesis of progressive supranuclear palsy (PSP) yet the specific intracellular defects which cause and can result from these oxidative and bioenergetic defects remain unclear. To extend our previous PSP cybrid findings, we measured electron transport chain (ETC) activities in cell lines expressing mitochondrial genes from patients with PSP. Further, we measured changes in mitochondrial membrane potential as well as lipid peroxidation in PSP and control cybrids in response to mitochondrial toxins. We observed significant decreases in complex I+III activity in PSP cybrids as well as significant increases in markers of lipid oxidative damage as compared to control cybrids. These results coupled with previous reports from this and other laboratories strongly suggest contributory roles of mitochondrial dysfunction and oxidative damage in PSP, possibly due to genetic abnormalities and/or damage of mitochondrial DNA.

Brain↗
PubMed2002

Expression and activity of antioxidants in the brain in progressive supranuclear palsy.

Recent evidence implicates oxidative stress in the pathophysiology of progressive supranuclear palsy (PSP). Thus, we undertook a study of the activity and localization of two essential antioxidant systems (superoxide dismutase [SOD] enzymes and total glutathione) in the human post-mortem PSP and control brain. Marked increases in SOD1 (Cu/ZnSOD) activity and glutathione levels were measured within most PSP brain regions examined, whereas, only the subthalamic nucleus exhibited a significant increase (+68%) in SOD2 (MnSOD) activity. Two additional cases with mild pathological abnormalities were studied. The first (case A) may represent an example of an asymptomatic PSP case, while the second (case B) had mild pathological abnormalities consistent with typical PSP. In case A, only the STN had elevated levels of SOD activity, in the absence of an increase in tissue glutathione content. In case B, SOD activities and tissue glutathione content were elevated in several regions. Immunolocalization of the SOD1 and SOD2 proteins in paraffin-embedded tissue sections revealed a marked increase in the density of SOD immunopositive profiles (particularly glia) in the typical PSP brain, particularly within the white matter. Together, our data argues strongly in favor of the involvement of oxidative stress in the etiology and progression of PSP, and suggests that deficit in SOD or glutathione metabolism are not causative.

Antioxidants↗
PubMed2002

Expression of MMP-2, MMP-9, and MMP-1 and their endogenous counterregulators TIMP-1 and TIMP-2 in postmortem brain tissue of Parkinson's disease.

We investigated the levels and tissue localization of matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) in postmortem brain tissue from Parkinson's disease (PD) and age-matched control cases. Using zymography, we found reduced MMP-2 levels in PD cases in the substantia nigra as compared to controls; levels of MMP-2 were not significantly changed in the cortex and the hippocampus. MMP-9 levels were unchanged in the investigated brain regions. Immunohistochemically, MMP-2 was localized primarily in astrocytes and microglia cells, whereas MMP-9 was predominantly neuronal. Levels of TIMP-1, an endogenous tissue inhibitor of MMPs, were significantly elevated in the substantia nigra, but not in the cortex and hippocampus. TIMP-2 levels were unchanged in PD. To investigate whether increased TIMP-1 levels in the substantia nigra might be due to increased MMP-1 expression, we measured MMP-1 levels using Western blots. MMP-1 levels were unchanged in PD cases compared to controls. Together, these data show alterations of MMP-2 and TIMP-1 in the substantia nigra of PD, consistent with the possibility that alterations in MMPs/TIMPs may contribute to disease pathogenesis.

Aged↗
PubMed2002

Mitochondrial dysfunction in progressive supranuclear palsy.

A progressive impairment of mitochondrial function has been suggested to play a critical role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. Mitochondrial dysfunction can lead to number of deleterious consequences including impaired calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition pore and secondary excitotoxicity. Progressive supranuclear palsy (PSP) is a rare neurological disorder characterized by the appearance of supranuclear gaze palsy and extrapyramidal symptoms [Arch. Neurol. 10 (1964) 333]. Although the etiological basis of PSP is unknown, compelling evidence from spectroscopy studies in PSP patients, biochemical studies in post-mortem PSP brain tissue and PSP cybrids has emerged that supports a contributory role of bio-energetic defects in the pathogenesis of PSP.

Humans↗