Abstract
In addition to the proteolytic cleavages that give rise to amyloid-β (Aβ), the amyloid-β protein precursor (AβPP) is cleaved at Asp664 intracytoplasmically. This cleavage releases a cytotoxic peptide, APP-C31, removes AβPP-interaction motifs required for signaling and internalization, and is required for the generation of AD-like deficits in a mouse model of the disease. Although we and others had previously shown that Asp664 cleavage of AβPP is increased in AD brains, the distribution of the Asp664-cleaved forms of AβPP in non-diseased and AD brains at different ages had not been determined. Confirming previous reports, we found that Asp664-cleaved forms of AβPP were increased in neuronal cytoplasm and nuclei in early-stage AD brains but were absent in age-matched, non-diseased control brains and in late-stage AD brains. Remarkably, however, Asp664-cleaved AβPP was prominent in neuronal somata and in processes in entorhinal cortex and hippocampus of non-diseased human brains at ages <45 years. Our observations suggest that Asp664 cleavage of AβPP may be part of the normal proteolytic processing of AβPP in young (<45 years) human brain and that this cleavage is down-regulated with normal aging, but is aberrantly increased and altered in location in early AD.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1-16 |
| Number of pages | 16 |
| Journal | Journal of Alzheimer's Disease |
| Volume | 13 |
| Issue number | 1 |
| State | Published - 2008 |
| Externally published | Yes |
Fingerprint
Keywords
- Alzheimer's disease
- Amyloid-β protein precursor
- APP-C31
- APPNeo
- Asp664
- Proteolytic processing
ASJC Scopus subject areas
- Neuropsychology and Physiological Psychology
Cite this
C-terminal cleavage of the amyloid-β protein precursor at Asp664 : A switch associated with Alzheimer's disease. / Banwait, Surita; Galvan Hart, Veronica; Zhang, Junli; Gorostiza, Olivia F.; Ataie, Marina; Huang, Wei; Crippen, Danielle; Koo, Edward H.; Bredesen, Dale E.
In: Journal of Alzheimer's Disease, Vol. 13, No. 1, 2008, p. 1-16.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - C-terminal cleavage of the amyloid-β protein precursor at Asp664
T2 - A switch associated with Alzheimer's disease
AU - Banwait, Surita
AU - Galvan Hart, Veronica
AU - Zhang, Junli
AU - Gorostiza, Olivia F.
AU - Ataie, Marina
AU - Huang, Wei
AU - Crippen, Danielle
AU - Koo, Edward H.
AU - Bredesen, Dale E.
PY - 2008
Y1 - 2008
N2 - In addition to the proteolytic cleavages that give rise to amyloid-β (Aβ), the amyloid-β protein precursor (AβPP) is cleaved at Asp664 intracytoplasmically. This cleavage releases a cytotoxic peptide, APP-C31, removes AβPP-interaction motifs required for signaling and internalization, and is required for the generation of AD-like deficits in a mouse model of the disease. Although we and others had previously shown that Asp664 cleavage of AβPP is increased in AD brains, the distribution of the Asp664-cleaved forms of AβPP in non-diseased and AD brains at different ages had not been determined. Confirming previous reports, we found that Asp664-cleaved forms of AβPP were increased in neuronal cytoplasm and nuclei in early-stage AD brains but were absent in age-matched, non-diseased control brains and in late-stage AD brains. Remarkably, however, Asp664-cleaved AβPP was prominent in neuronal somata and in processes in entorhinal cortex and hippocampus of non-diseased human brains at ages <45 years. Our observations suggest that Asp664 cleavage of AβPP may be part of the normal proteolytic processing of AβPP in young (<45 years) human brain and that this cleavage is down-regulated with normal aging, but is aberrantly increased and altered in location in early AD.
AB - In addition to the proteolytic cleavages that give rise to amyloid-β (Aβ), the amyloid-β protein precursor (AβPP) is cleaved at Asp664 intracytoplasmically. This cleavage releases a cytotoxic peptide, APP-C31, removes AβPP-interaction motifs required for signaling and internalization, and is required for the generation of AD-like deficits in a mouse model of the disease. Although we and others had previously shown that Asp664 cleavage of AβPP is increased in AD brains, the distribution of the Asp664-cleaved forms of AβPP in non-diseased and AD brains at different ages had not been determined. Confirming previous reports, we found that Asp664-cleaved forms of AβPP were increased in neuronal cytoplasm and nuclei in early-stage AD brains but were absent in age-matched, non-diseased control brains and in late-stage AD brains. Remarkably, however, Asp664-cleaved AβPP was prominent in neuronal somata and in processes in entorhinal cortex and hippocampus of non-diseased human brains at ages <45 years. Our observations suggest that Asp664 cleavage of AβPP may be part of the normal proteolytic processing of AβPP in young (<45 years) human brain and that this cleavage is down-regulated with normal aging, but is aberrantly increased and altered in location in early AD.
KW - Alzheimer's disease
KW - Amyloid-β protein precursor
KW - APP-C31
KW - APPNeo
KW - Asp664
KW - Proteolytic processing
UR - http://www.scopus.com/inward/record.url?scp=40549095365&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=40549095365&partnerID=8YFLogxK
M3 - Article
C2 - 18334752
AN - SCOPUS:40549095365
VL - 13
SP - 1
EP - 16
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 1
ER -