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Pharmacopsychiatry 2003; 36: 120-126
DOI: 10.1055/s-2003-43060
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Cholesterol and Tau Protein - Findings in Alzheimer’s and Niemann Pick C’s Disease

T. G. Ohm1 , S. Treiber-Held1 , R. Distl1 , F. Glöckner1 , B. Schönheit1 , M. Tamanai1 , V. Meske1
  • 1Institute of Anatomy, Department of Clinical Cell- and Neurobiology, Charité, Humboldt University, Berlin, Germany
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Publication Date:
22 October 2003 (online)

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Niemann Pick C (NPC), a fatal autosomal-recessive neurovisceral lipid storage disorder, is a juvenile dementia with massive nerve-cell loss and cytoskeletal abnormalities in cerebral neurons. These abnormalities consist of tangles of tau protein, which is otherwise highly soluble and usually stabilizes the microtubules. Immunologically and ultrastructurally similar tangles are seen some decades later in patients with Alzheimer’s disease (AD). There is evidence that tangle-bearing cells in both diseases show higher levels of free (i. e. filipin-positive) cholesterol than adjacent tangle-free nerve cells. The cholesterol accumulates either in a more diffuse way (mainly in AD) or in granule-like accumulations (mainly in NPC). In NPC, neuron cholesterol may originate from sources other than the alimentary tract. Experiments with a NPC mouse model revealed that even in pure neuron cultures, the NPC -/- neurons accumulate free cholesterol in contrast to NPC-wt littermates, suggesting that the cholesterol is either synthesized by the neurons or liberated from degenerated ones before being taken up by the endosomal/lysosomal pathway. The accumulation of free cholesterol in the somata of NPC neurons is associated with a decrease of cholesterol levels in myelin sheaths. In terms of tau protein, NPC -/- mice exhibit higher levels of AT8-positive tau, suggesting that the phosphorylation-dependent mAb AT8 has detected a tau-epitope in a state considered to represent early stages of tangle formation. Concomitantly to the increase in free intracellular cholesterol, the rate-limiting enzyme in cholesterol and isoprenoid biosynthesis, HMG-CoA reductase, was found to be significantly reduced. Experimental blockade of the enzyme’s activity by application of the lipid-lowering drug lovastatin showed subcellular shifts in tau phosphorylation as monitored with mAbs AT8, 12E8 and others. In summary, the data showed interesting similarities between NPC and AD suggesting some pathological metabolic pathway in common.

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Thomas G. Ohm

Institute of Anatomy

Department of Clinical Cell- and Neurobiology

Charité

10098 Berlin

Germany

Phone: +49-30-450-528202

Fax: +49-30-450-528913

Email: thomas_georg.ohm@charite.de

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