Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice.
In the brain of Alzheimer's disease (AD) patients, neurotoxic amyloid peptides accumulate and are deposited as senile plaques. A major therapeutic strategy aims to decrease production of amyloid peptides by inhibition of gamma-secretase. Presenilins are polytopic transmembrane proteins that are essential for gamma-secretase activity during development and in amyloid production. By loxP/Cre-recombinase-mediated deletion, we generated mice with postnatal, neuron-specific presenilin-1 (PS1) deficiency, denoted PS1(n-/-), that were viable and fertile, with normal brain morphology. In adult PS1(n-/-) mice, levels of endogenous brain amyloid peptides were strongly decreased, concomitant with accumulation of amyloid precursor protein (APP) C-terminal fragments. In the cross of APP[V717I]xPS1 (n-/-) double transgenic mice, the neuronal absence of PS1 effectively prevented amyloid pathology, even in mice that were 18 months old. This contrasted sharply with APP[V717I] single transgenic mice that all develop amyloid pathology at the age of 10-12 months. In APP[V717I]xPS1 (n-/-) mice, long-term potentiation (LTP) was practically rescued at the end of the 2 hr observation period, again contrasting sharply with the strongly impaired LTP in APP[V717I] mice. The findings demonstrate the critical involvement of amyloid peptides in defective LTP in APP transgenic mice. Although these data open perspectives for therapy of AD by gamma-secretase inhibition, the neuronal absence of PS1 failed to rescue the cognitive defect, assessed by the object recognition test, of the parent APP[V717I] transgenic mice. This points to potentially detrimental effects of accumulating APP C99 fragments and demands further study of the consequences of inhibition of gamma-secretase activity. In addition, our data highlight the complex functional relation of APP and PS1 to cognition and neuronal plasticity in adult and aging brain.
Dewachter
Ilse
I
Experimental Genetics Group, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium, Laboratory of Neuroscience, University of Mons-Hainaut, 7000 Mons, Belgium.
Reversé
Delphine
D
Caluwaerts
Nathalie
N
Ris
Laurence
L
Kuipéri
Cuno
C
Van den Haute
Chris
C
Spittaels
Kurt
K
Umans
Lieve
L
Serneels
Lutgarde
L
Thiry
Els
E
Moechars
Dieder
D
Mercken
Mark
M
Godaux
Emile
E
Van Leuven
Fred
F
D000544:Alzheimer Disease / Q000209:etiology; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004558:Electric Stimulation; D010450:Endopeptidases / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D017774:Long-Term Potentiation / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1; D012333:RNA, Messenger / Q000378:metabolism; D021641:Recognition, Psychology; D012097:Repressor Proteins / Q000378:metabolism
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D010450:Endopeptidases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; D012333:RNA, Messenger; D012097:Repressor Proteins; C489685:Hes5 protein, mouse; C064045:delta protein; C509282:Bace1 protein, mouse