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Intraneuronal pyroglutamate-Abeta 3-42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model.

Wirths O, Breyhan H, Cynis H, Schilling S, Demuth HU, Bayer TA - Acta Neuropathol. (2009)

Bottom Line: When compared with Abeta(1-42), this peptide has stronger aggregation propensity and increased toxicity in vitro.Although TBA2 transgenic mice exhibit a strong neuronal expression of Abeta(3-42) predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus.Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrates that intraneuronal Abeta(3(pE)-42) is neurotoxic in vivo.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Psychiatry, Department of Psychiatry, University of Goettingen, Von-Siebold-Strasse 5, Goettingen, Germany.

ABSTRACT
It is well established that only a fraction of Abeta peptides in the brain of Alzheimer's disease (AD) patients start with N-terminal aspartate (Abeta(1D)) which is generated by proteolytic processing of amyloid precursor protein (APP) by BACE. N-terminally truncated and pyroglutamate modified Abeta starting at position 3 and ending with amino acid 42 [Abeta(3(pE)-42)] have been previously shown to represent a major species in the brain of AD patients. When compared with Abeta(1-42), this peptide has stronger aggregation propensity and increased toxicity in vitro. Although it is unknown which peptidases remove the first two N-terminal amino acids, the cyclization of Abeta at N-terminal glutamate can be catalyzed in vitro. Here, we show that Abeta(3(pE)-42) induces neurodegeneration and concomitant neurological deficits in a novel mouse model (TBA2 transgenic mice). Although TBA2 transgenic mice exhibit a strong neuronal expression of Abeta(3-42) predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus. The levels of converted Abeta(3(pE)-42) in TBA2 mice were comparable to the APP/PS1KI mouse model with robust neuron loss and associated behavioral deficits. Eight weeks after birth TBA2 mice developed massive neurological impairments together with abundant loss of Purkinje cells. Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrates that intraneuronal Abeta(3(pE)-42) is neurotoxic in vivo.

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Sequence of Aβ1–42 and N-terminal truncated Aβ starting at position 3. a Aβ1–42 starts at position 1 with aspartate (D), Aβ3E–42 at position 3 with glutamate (E), and Aβ3Q–42 with glutamine (Q). Both N-truncated Aβ3E–42 and Aβ3Q–42 peptides can be converted into pyroglutamate-Aβ3(pE)–42. b Schematic drawing of the transgenic vector. TBA2 transgenic mice express Aβ3(Q)–42 under the control of the Thy1 promoter fused to the signal peptide of the pre-pro-thyrotropin-releasing hormone. c N-terminal Aβ starting with glutamate (Aβ3E) or glutamine (Aβ3Q) at position 3 serves as substrates for generation of Aβ3(pE). The conversion of pyroglutamate from N-terminal glutamate (E) is slow, in contrast to fast pyroglutamate (pE) formation from glutamine (Q) [12]
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Fig1: Sequence of Aβ1–42 and N-terminal truncated Aβ starting at position 3. a Aβ1–42 starts at position 1 with aspartate (D), Aβ3E–42 at position 3 with glutamate (E), and Aβ3Q–42 with glutamine (Q). Both N-truncated Aβ3E–42 and Aβ3Q–42 peptides can be converted into pyroglutamate-Aβ3(pE)–42. b Schematic drawing of the transgenic vector. TBA2 transgenic mice express Aβ3(Q)–42 under the control of the Thy1 promoter fused to the signal peptide of the pre-pro-thyrotropin-releasing hormone. c N-terminal Aβ starting with glutamate (Aβ3E) or glutamine (Aβ3Q) at position 3 serves as substrates for generation of Aβ3(pE). The conversion of pyroglutamate from N-terminal glutamate (E) is slow, in contrast to fast pyroglutamate (pE) formation from glutamine (Q) [12]

Mentions: In addition to Aβ starting with aspartate at position 1 (Aβ1D), one major Aβ species in AD brain starts at position 3 with pyroglutamate (Aβ3(pE)) that can be converted from N-terminal glutamate (Aβ3E) or glutamine (Aβ3Q) (Fig. 1a). We generated a novel mouse model that expresses Aβ3–42 peptides under the control of the Thy-1 promoter. The TBA2 line expresses Aβ with N-terminal glutamine (Aβ3Q–42) as a fusion protein with the pre-pro-sequence of murine thyrotropin-releasing hormone (mTRH) (Fig. 1b), for transport via the secretory pathway [12].Fig. 1


Intraneuronal pyroglutamate-Abeta 3-42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model.

Wirths O, Breyhan H, Cynis H, Schilling S, Demuth HU, Bayer TA - Acta Neuropathol. (2009)

Sequence of Aβ1–42 and N-terminal truncated Aβ starting at position 3. a Aβ1–42 starts at position 1 with aspartate (D), Aβ3E–42 at position 3 with glutamate (E), and Aβ3Q–42 with glutamine (Q). Both N-truncated Aβ3E–42 and Aβ3Q–42 peptides can be converted into pyroglutamate-Aβ3(pE)–42. b Schematic drawing of the transgenic vector. TBA2 transgenic mice express Aβ3(Q)–42 under the control of the Thy1 promoter fused to the signal peptide of the pre-pro-thyrotropin-releasing hormone. c N-terminal Aβ starting with glutamate (Aβ3E) or glutamine (Aβ3Q) at position 3 serves as substrates for generation of Aβ3(pE). The conversion of pyroglutamate from N-terminal glutamate (E) is slow, in contrast to fast pyroglutamate (pE) formation from glutamine (Q) [12]
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2737116&req=5

Fig1: Sequence of Aβ1–42 and N-terminal truncated Aβ starting at position 3. a Aβ1–42 starts at position 1 with aspartate (D), Aβ3E–42 at position 3 with glutamate (E), and Aβ3Q–42 with glutamine (Q). Both N-truncated Aβ3E–42 and Aβ3Q–42 peptides can be converted into pyroglutamate-Aβ3(pE)–42. b Schematic drawing of the transgenic vector. TBA2 transgenic mice express Aβ3(Q)–42 under the control of the Thy1 promoter fused to the signal peptide of the pre-pro-thyrotropin-releasing hormone. c N-terminal Aβ starting with glutamate (Aβ3E) or glutamine (Aβ3Q) at position 3 serves as substrates for generation of Aβ3(pE). The conversion of pyroglutamate from N-terminal glutamate (E) is slow, in contrast to fast pyroglutamate (pE) formation from glutamine (Q) [12]
Mentions: In addition to Aβ starting with aspartate at position 1 (Aβ1D), one major Aβ species in AD brain starts at position 3 with pyroglutamate (Aβ3(pE)) that can be converted from N-terminal glutamate (Aβ3E) or glutamine (Aβ3Q) (Fig. 1a). We generated a novel mouse model that expresses Aβ3–42 peptides under the control of the Thy-1 promoter. The TBA2 line expresses Aβ with N-terminal glutamine (Aβ3Q–42) as a fusion protein with the pre-pro-sequence of murine thyrotropin-releasing hormone (mTRH) (Fig. 1b), for transport via the secretory pathway [12].Fig. 1

Bottom Line: When compared with Abeta(1-42), this peptide has stronger aggregation propensity and increased toxicity in vitro.Although TBA2 transgenic mice exhibit a strong neuronal expression of Abeta(3-42) predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus.Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrates that intraneuronal Abeta(3(pE)-42) is neurotoxic in vivo.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Psychiatry, Department of Psychiatry, University of Goettingen, Von-Siebold-Strasse 5, Goettingen, Germany.

ABSTRACT
It is well established that only a fraction of Abeta peptides in the brain of Alzheimer's disease (AD) patients start with N-terminal aspartate (Abeta(1D)) which is generated by proteolytic processing of amyloid precursor protein (APP) by BACE. N-terminally truncated and pyroglutamate modified Abeta starting at position 3 and ending with amino acid 42 [Abeta(3(pE)-42)] have been previously shown to represent a major species in the brain of AD patients. When compared with Abeta(1-42), this peptide has stronger aggregation propensity and increased toxicity in vitro. Although it is unknown which peptidases remove the first two N-terminal amino acids, the cyclization of Abeta at N-terminal glutamate can be catalyzed in vitro. Here, we show that Abeta(3(pE)-42) induces neurodegeneration and concomitant neurological deficits in a novel mouse model (TBA2 transgenic mice). Although TBA2 transgenic mice exhibit a strong neuronal expression of Abeta(3-42) predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus. The levels of converted Abeta(3(pE)-42) in TBA2 mice were comparable to the APP/PS1KI mouse model with robust neuron loss and associated behavioral deficits. Eight weeks after birth TBA2 mice developed massive neurological impairments together with abundant loss of Purkinje cells. Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrates that intraneuronal Abeta(3(pE)-42) is neurotoxic in vivo.

Show MeSH
Related in: MedlinePlus