Tauopathy-Associated Tau Fragment Ending at Amino Acid 224 Is Generated by Calpain-2 Cleavage.

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Tauopathy-Associated Tau Fragment Ending at Amino Acid 224 Is Generated by Calpain-2 Cleavage.

Cicognola, Claudia (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Satir, Tugce Munise (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Brinkmalm, Gunnar (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Matečko-Burmann, Irena (author): Gothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine

Agholme, Lotta (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Bergström, Petra (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Becker, Bruno, 1961 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Zetterberg, Henrik, 1973 (author): Gothenburg University,Göteborgs universitet,Centrum för åldrande och hälsa (AgeCap),Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Centre for Ageing and Health (Agecap),Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Blennow, Kaj, 1958 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Centrum för åldrande och hälsa (AgeCap),Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry,Centre for Ageing and Health (Agecap)

Höglund, Kina, 1976 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Centrum för åldrande och hälsa (AgeCap),Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry,Centre for Ageing and Health (Agecap)

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2020
2020
English.
In: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 74:4, s. 1143-1156

Related links:: https://gup.ub.gu.se...; show more...; https://doi.org/10.3...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

Tau aggregation in neurons and glial cells characterizes tauopathies as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Tau proteolysis has been proposed as a trigger for tau aggregation and tau fragments have been observed in brain and cerebrospinal fluid (CSF). Our group identified a major tau cleavage at amino acid (aa) 224 in CSF; N-terminal tau fragments ending at aa 224 (N-224) were significantly increased in AD and lacked correlation to total tau (t-tau) and phosphorylated tau (p-tau) in PSP and CBD.Previous studies have shown cleavage from calpain proteases at sites adjacent to aa 224. Our aim was to investigate if calpain-1 or -2 could be responsible for cleavage at aa 224.Proteolytic activity of calpain-1, calpain-2, and brain protein extract was assessed on a custom tau peptide (aa 220-228), engineered with fluorescence resonance energy transfer (FRET) technology. Findings were confirmed with in-gel trypsination and mass spectrometry (MS) analysis of brain-derived bands with proteolytic activity on the FRET substrate. Finally, knock-down of the calpain-2 catalytic subunit gene (CAPN2) was performed in a neuroblastoma cell line (SH-SY5Y).Calpain-2 and brain protein extract, but not calpain-1, showed proteolytic activity on the FRET substrate. MS analysis of active gel bands revealed presence of calpain-2 subunits, but not calpain-1. Calpain-2 depletion and chemical inhibition suppressed proteolysis of the FRET substrate. CAPN2 knock-down caused a 76.4% reduction of N-224 tau in the cell-conditioned media.Further investigation of the calpain-2 pathway in the pathogenesis of tauopathies is encouraged.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine (hsv//eng)

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine

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By the university: University of Gothenburg

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