TY - JOUR
T1 - Reversal of learning deficits in hAPP transgenic mice carrying a mutation at Asp664
T2 - A role for early experience
AU - Zhang, Junli
AU - Gorostiza, Olivia F.
AU - Tang, Huidong
AU - Bredesen, Dale E.
AU - Galvan, Veronica
N1 - Funding Information:
We thank Ms. Katrine N. Krueger for excellent administrative assistance. Supported in part by Alzheimer's Association NIRG 04-1054 to V.G., NIHNS1027-04-01 to D.B., a Drown Foundation award to D.B., IIRG 06-27717 to D.B. and an award from S.D. Bechtel, Jr. to V.G.
PY - 2010/1/20
Y1 - 2010/1/20
N2 - In addition to the cleavages that generate amyloid-beta (Aβ), the Aβ-precursor protein (APP) is processed at Asp664, releasing a second toxic peptide (APP-C31). Transgenic mice otherwise identical to a well-characterized model of AD, PDAPP mice, but carrying a mutation that obliterates Asp664 show a reversal of AD-like deficits in memory and in non-cognitive components of behaviour in spite of accumulating high levels of Aβ. These results suggest that cleavage of APP at Asp664 plays a role in the generation of AD-like deficits, and that a major pathway of Aβ toxicity in vivo, or a pathway that crucially impinges on it, may depend on cleavage of APP at Asp664. Since young PDAPP(D664A) mice showed an akinetic phenotype when first required to swim, we trained a 3-month-old (mo) cohort to criterion (normal swimming), and briefly exposed it to the Morris water maze (MWM) environment prior to training at 7 mo, to avoid potentially confounding effects of the akinetic phenotype in MWM studies. Prior experience decreased floating in PDAPP(D664A) mice but not in PDAPP nor in non-Tg groups. While learning was restored in experienced PDAPP(D664A) mice, it was indistinguishable from both non-Tg as well as from PDAPP mice in naïve PDAPP(D664A) animals. Floating did not correlate with worse performance in naïve PDAPP(D664A) mice, suggesting that the contribution of prior experience to improved performance is related to its cognitive effects but not to non-cognitive components of behaviour. Our results suggest that early experience reduces the contribution of non-cognitive components of behaviour to performance, and may contribute to the restoration of learning at later ages in PDAPP(D664A) mice.
AB - In addition to the cleavages that generate amyloid-beta (Aβ), the Aβ-precursor protein (APP) is processed at Asp664, releasing a second toxic peptide (APP-C31). Transgenic mice otherwise identical to a well-characterized model of AD, PDAPP mice, but carrying a mutation that obliterates Asp664 show a reversal of AD-like deficits in memory and in non-cognitive components of behaviour in spite of accumulating high levels of Aβ. These results suggest that cleavage of APP at Asp664 plays a role in the generation of AD-like deficits, and that a major pathway of Aβ toxicity in vivo, or a pathway that crucially impinges on it, may depend on cleavage of APP at Asp664. Since young PDAPP(D664A) mice showed an akinetic phenotype when first required to swim, we trained a 3-month-old (mo) cohort to criterion (normal swimming), and briefly exposed it to the Morris water maze (MWM) environment prior to training at 7 mo, to avoid potentially confounding effects of the akinetic phenotype in MWM studies. Prior experience decreased floating in PDAPP(D664A) mice but not in PDAPP nor in non-Tg groups. While learning was restored in experienced PDAPP(D664A) mice, it was indistinguishable from both non-Tg as well as from PDAPP mice in naïve PDAPP(D664A) animals. Floating did not correlate with worse performance in naïve PDAPP(D664A) mice, suggesting that the contribution of prior experience to improved performance is related to its cognitive effects but not to non-cognitive components of behaviour. Our results suggest that early experience reduces the contribution of non-cognitive components of behaviour to performance, and may contribute to the restoration of learning at later ages in PDAPP(D664A) mice.
KW - Alzheimer's disease
KW - Asp664 cleavage
KW - Learning
KW - Morris water maze
KW - Non-cognitive components of behaviour
KW - Transgenic mouse model
UR - http://www.scopus.com/inward/record.url?scp=70350324313&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70350324313&partnerID=8YFLogxK
U2 - 10.1016/j.bbr.2009.09.013
DO - 10.1016/j.bbr.2009.09.013
M3 - Article
C2 - 19751769
AN - SCOPUS:70350324313
VL - 206
SP - 202
EP - 207
JO - Behavioural Brain Research
JF - Behavioural Brain Research
SN - 0166-4328
IS - 2
ER -