S1 pocket of glutamate carboxypeptidase II: A new binding site for amyloid-β degradation

Glutamate carboxypeptidase II (GCPII) expression in brain is increased by inflammation, and reduces NAAG (N-acetyl aspartyl glutamate) stimulation of mGluR3 signaling. Genetic insults in this signaling cascade are increasingly linked to cognitive disorders in humans, where increased GCPII and or decreased NAAG-mGluR3 are associated with impaired prefrontal cortical (PFC) activation and cognitive impairment. As aging is associated with increased inflammation and PFC cognitive deficits, the current study examined GCPII and mGluR3 expression in the aging rat medial PFC, and tested whether GCPII inhibition with 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) would improve working memory performance. We found that GCPII protein was expressed on astrocytes and some microglia as expected from previous studies, but was also prominently expressed on neurons, and showed increased levels with advancing age. Systemic administration of the GCPII inhibitor, 2-MPPA, improved working memory performance in young and aged rats, and also improved performance after local infusion into the medial PFC. As GCPII inhibitors are well-tolerated, they may provide an important new direction for treatment of cognitive disorders associated with aging and/or inflammation.

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Glutamate carboxypeptidase II (GCPII) inhibitor 2-PMPA reduces rewarding effects of the synthetic cathinone MDPV in rats: a role for N-acetylaspartylglutamate (NAAG)

Psychopharmacology ◽

10.1007/s00213-017-4568-y ◽

2017 ◽

Vol 234 (11) ◽

pp. 1671-1681 ◽

Cited By ~ 10

Author(s):

Callum Hicks ◽

Ryan A. Gregg ◽

Sunil U. Nayak ◽

Lee Anne Cannella ◽

Giana J. Schena ◽

...

Keyword(s):

Glutamate Carboxypeptidase Ii ◽

Synthetic Cathinone ◽

Glutamate Carboxypeptidase

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Glutamate Carboxypeptidase II Inhibition Behaviorally and Physiologically Improves Pyridoxine-Induced Neuropathy in Rats

PLoS ONE ◽

10.1371/journal.pone.0102936 ◽

2014 ◽

Vol 9 (9) ◽

pp. e102936 ◽

Cited By ~ 8

Author(s):

Michelle C. Potter ◽

Krystyna M. Wozniak ◽

Noelle Callizot ◽

Barbara S. Slusher

Keyword(s):

Glutamate Carboxypeptidase Ii ◽

Glutamate Carboxypeptidase

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Apolipoprotein E includes a binding site which is recognized by several amyloidogenic polypeptides

Biochemical Journal ◽

10.1042/bj3490077 ◽

2000 ◽

Vol 349 (1) ◽

pp. 77-84 ◽

Cited By ~ 10

Author(s):

Marc H. BAUMANN ◽

Jukka KALLIJÄRVI ◽

Hilkka LANKINEN ◽

Claudio SOTO ◽

Matti HALTIA

Keyword(s):

Apolipoprotein E ◽

Binding Site ◽

Late Onset ◽

Specific Binding ◽

Prion Diseases ◽

Amyloid Β ◽

Structural Motif ◽

Amyloid Β Peptide ◽

High Avidity ◽

Amyloidogenic Protein

Inheritance of the apolipoprotein E (apoE) ϵ4 allele is a risk factor for late-onset Alzheimer's disease (AD). Biochemically apoE is present in AD plaques and neurofibrillary tangles of the AD brain. There is a high avidity and specific binding of apoE and the amyloid β-peptide (Aβ). In addition to AD apoE is also present in many other cerebral and systemic amyloidoses, Down's syndrome and prion diseases but the pathophysiological basis for its presence is still unknown. In the present study we have compared the interaction of apoE with Aβ, the gelsolin-derived amyloid fragment AGel183-210 and the amyloidogenic prion fragments PrP109-122 and PrP109-141. We show that, similar to Aβ, also AGel and PrP fragments can form a complex with apoE, and that the interaction between apoE and the amyloidogenic protein fragments is mediated through the same binding site on apoE. We also show that apoE increases the thioflavin-T fluorescence of PrP and AGel and that apoE influences the content of β-sheet conformation of these amyloidogenic fragments. Our results indicate that amyloids and amyloidogenic prion fragments share a similar structural motif, which is recognized by apoE, possibly through a single binding site, and that this motif is also responsible for the amyloidogenicity of these fragments.

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