Alzheimer Disease: Mandal PK

Mandal PK, Fodale V. · Neurospectroscopy and Neuroimaging Laboratory, National Brain Research Centre, Manesar, Gurgaon, India. · Biochem Biophys Res Commun. · Pubmed #19116131 No free full text.

Abstract: Current understanding on Alzheimer's disease (AD) reveals that soluble amyloid beta-peptide (Abeta) oligomeric formation plays an important role in AD pathophysiology. A potential role for several inhaled anesthetics in promoting Abeta oligomer formation has been suggested. Using a nuclear magnetic resonance (NMR) study, we previously demonstrated that at a high concentration (higher than clinically relevant concentrations), the inhaled anesthetics halothane and isoflurane, interact with specific amino acid residues (G29, A30, and I31) and induce Abeta oligomerization. The present study confirms this is true at a clinically relevant concentration. Isoflurane and desflurane induce Abeta oligomerization by inducing chemical shift changes of the critical amino acid residues (G29, A30, and I31), reinforcing the evidence that perturbation of these three crucial residues indeed plays an important role in oligomerization. These findings support the emerging hypothesis that several commonly used inhaled anesthetics could be involved in neurodegeneration, as well as risk factor for accelerating the onset of AD.

Mandal PK, Pettegrew JW, Masliah E, Hamilton RL, Mandal R. · Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, 3811 O'Hara Street, Pittsburgh, PA 15213, USA. · Neurochem Res. · Pubmed #16947080 No free full text.

Abstract: Amyloidogenic proteins (Abeta peptide) in Alzheimer's disease (AD) and alpha-synuclein (alpha-Syn) in Parkinson's disease (PD) are typically soluble monomeric precursors, which undergo remarkable conformational changes and culminate in the form of aggregates in diseased condition. Overlap of clinical and neuropathological features of both AD and PD are observed in dementia with Lewy body (DLB) disease, the second most common form of dementia after AD. The identification of a 35-amino acid fragment of alpha-Syn in the amyloid plaques in DLB brain have raised the possibility that Abeta and alpha-Syn interact with each other. In this report, the molecular interaction of alpha-Syn with Abeta40 and/or Abeta42 are investigated using multidimensional NMR spectroscopy. NMR data in the membrane mimic environment indicate specific sites of interaction between membrane-bound alpha-Syn with Abeta peptide and vice versa. These Abeta-alpha-Syn interactions are demonstrated by reduced amide peak intensity or change in chemical shift of amide proton of the interacting proteins. Based on NMR results, the plausible molecular mechanism of overlapping pathocascade of AD and PD in DLB due to interactions between alpha-Syn and Abeta is described. To the best of our knowledge, it is the first report using multidimensional NMR spectroscopy that elucidates molecular interactions between Abeta and alpha-Syn which may lead to onset of DLB.

Mandal PK, McClure RJ, Pettegrew JW. · Neurophysics Laboratory, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA. · Neurochem Res. · Pubmed #15672550 No free full text.

Abstract: Deposition of amyloid beta peptide in human brain in the form of senile plaques is a neuropathological hallmark of Alzheimer's disease (AD). Levels of a phospholipid breakdown product, glycerophosphocholine (GPC), also increase in AD brain. The effect of GPC on amyloid beta(1-40) peptide (Abeta) aggregation in PBS buffer was investigated by circular dichroism and fluoresence spectroscopy; interactions of Abeta and GPC with the intact erythrocyte membrane was examined by fluoresence spectroscopy. Fluorescamine labeled Abeta studies indicate GPC enhances Abeta aggregation. CD spectroscopy reveals that Abeta in the presence of GPC adopts 14% more beta-sheet structure than does Abeta alone. Fluorescamine anisotropy measurements show that GPC and Abeta interact in the phospholipid head-group region of the erythrocyte membrane. In summary, both soluble Abeta and GPC insert into the phospholipid head-group region of the membrane where they interact leading to beta-sheet formation in soluble Abeta which enhances Abeta aggregation.

Mandal PK, Pettegrew JW. · Neurophysics Laboratory, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. · Neurochem Res. · Pubmed #15672549 No free full text.

Abstract: Amyloid beta peptide (Abeta) is a small peptide present in normal cells and aggregated Abeta is the main constituent of the extracellular amyloid plaques found in Alzheimer's disease (AD) brain. Recent studies suggest that soluble Abeta oligomers are neurotoxic rather than amyloid fibrils found in amyloid plaques. This study using multidimensional NMR spectroscopy and circular dichroism (CD) provides the first direct evidence that alterations in membrane structure can trigger the conversion of soluble alpha-helical monomeric Abeta into oligomeric Abeta in a beta-sheet conformation.

Mandal PK, Pettegrew JW. · Laboratory of Neurophysics, Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania 15261, USA. · Neurochem Res. · Pubmed #15002743 No free full text.

Abstract: Amyloid peptide (Abeta) is the major protein constituent of neuritic plaques in Alzheimer's disease (AD). This peptide is an amphipathic molecule that perturbs membranes and binds to raft-like membranes composed of gangliosides. Ganglioside GM1 binds tightly with Abeta and it is speculated that GM1 inhibits Abeta from undergoing alpha-helix to beta-sheet conformational changes. Although the role of gangliosides in conformational changes of Abeta have been studied, the specific nature of these interactions have not been reported. In the present report multidimensional NMR studies of ganglioside-Abeta interactions were conducted in sodium dodecyl sulphate (SDS) micelles, a membrane-mimicking environment. These studies reveal that asialoGM1 binds specifically with Abeta in a manner which could prevent beta-sheet formation. but that ganglioside GT1b does not bind Abeta. Plausible pathways for the involvement of gangliosides in amyloidogenesis are discussed.

Mandal PK, Pettegrew JW. · No affiliation provided · Neurochem Res. · Pubmed #18049892 No free full text.

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Mandal PK, Pettegrew JW, McKeag DW, Mandal R. · Western Psychiatric Institute and Clinic Department of Psychiatry, University of Pittsburgh Medical School, 3811 O'Hara Street, PA 15213, USA. · Neurochem Res. · Pubmed #16807784 No free full text.

Abstract: Alzheimer's disease (AD) is a significant contributor to cognitive decline and is responsible for about half of the cases of dementia in later life. Although exact etiology of AD is not known, however, many risk factors for AD are identified. Anesthesia for elderly patients is considered as a risk factor in AD as they frequently experience deterioration in cognitive function with long exposure to anesthetics during surgery. Inhaled anesthetic agents remain the mainstay for patients undergoing major surgical operations. This study using multidimensional NMR spectroscopy provides the first direct evidence in vitro that inhaled anesthetic, halothane specifically interacts with Abeta40 and Abeta42 peptide. Halothane induces structural alternation of Abeta peptide from soluble monomeric alpha-helical form to oligomeric beta-sheet conformation, which may hasten the onset of AD. Abeta42 is more prone to oligomerization compared to Abeta40 in the presence of halothane. The molecular mechanism of halothane induced structural alternation of Abeta peptide is discussed.