Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits.
Transgenic mice expressing human amyloid precursor proteins (hAPP) and amyloid-beta peptides (Abeta) in neurons develop phenotypic alterations resembling Alzheimer's disease (AD). The mechanisms underlying cognitive deficits in AD and hAPP mice are largely unknown. We have identified two molecular alterations that accurately reflect AD-related cognitive impairments. Learning deficits in mice expressing familial AD-mutant hAPP correlated strongly with decreased levels of the calcium-binding protein calbindin-D28k (CB) and the calcium-dependent immediate early gene product c-Fos in granule cells of the dentate gyrus, a brain region critically involved in learning and memory. These molecular alterations were age-dependent and correlated with the relative abundance of Abeta1-42 but not with the amount of Abeta deposited in amyloid plaques. CB reductions in the dentate gyrus primarily reflected a decrease in neuronal CB levels rather than a loss of CB-producing neurons. CB levels were also markedly reduced in granule cells of humans with AD, even though these neurons are relatively resistant to AD-related cell death. Thus, neuronal populations resisting cell death in AD and hAPP mice can still be drastically altered at the molecular level. The tight link between Abeta-induced cognitive deficits and neuronal depletion of CB and c-Fos suggests an involvement of calcium-dependent pathways in AD-related cognitive decline and could facilitate the preclinical evaluation of novel AD treatments.
Palop
Jorge J
JJ
Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, CA 94141, USA.
Jones
Brian
B
Kekonius
Lisa
L
Chin
Jeannie
J
Yu
Gui-Qiu
GQ
Raber
Jacob
J
Masliah
Eliezer
E
Mucke
Lennart
L
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D018891:Dentate Gyrus / Q000378:metabolism*; D005260:Female; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000682:Amyloid; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D002118:Calcium