Sp3 and sp4 transcription factor levels are increased in brains of patients with Alzheimer's disease.
OBJECTIVE
Alzheimer's disease (AD) is characterized by extracellular Abeta peptide deposition originating from amyloid precursor protein cleavage and intracellular neurofibrillary tangles resulting from pathological tau protein aggregation. These processes are accompanied by dramatic neuronal losses, further leading to different cognitive impairments. Neuronal death signalings involve gene expression modifications that rely on transcription factor alterations. Herein, we investigated the fate of the Sp family of transcription factors in postmortem brains from patients with AD disease and in different contexts of neuronal death.


RESULTS
By immunohistochemistry we found that the Sp3 and Sp4 levels were dramatically increased and associated with neurofibrillary tangles and pathological tau presence in neurons from the CA1 region of the hippocampus, as well as the entorhinal cortex of AD patient brains. The Sp transcription factor expression levels were further analyzed in cortical neurons in which death is induced by amyloid precursor protein signaling targeting. While the Sp1 levels remained constant, the Sp4 levels were slightly upregulated in response to the death signal. The Sp3 isoforms were rather degraded. Interestingly, when overexpressed by transfection experiments, the three Sp family members induced neuronal apoptosis, Sp3 and Sp4 being the most potent proapoptotic factors over Sp1.


CONCLUSIONS
Our data evidence Sp3 and Sp4 as new hallmarks of AD in postmortem human brains and further point out that Sp proteins are potential triggers of neuronal death signaling cascades.
Boutillier
Stéphanie
S
Inserm, U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg, France.
Lannes
Béatrice
B
Buée
Luc
L
Delacourte
André
A
Rouaux
Caroline
C
Mohr
Michel
M
Bellocq
Jean-Pierre
JP
Sellal
François
F
Larmet
Yves
Y
Boutillier
Anne-Laurence
AL
Loeffler
Jean-Philippe
JP
D000544:Alzheimer Disease / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D011180:Postmortem Changes; D051705:Sp3 Transcription Factor / Q000378:metabolism*; D051706:Sp4 Transcription Factor / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D016875:tau Proteins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D007976:Leupeptins; D009842:Oligopeptides; C497121:SP3 protein, human; C497124:SP4 protein, human; D051706:Sp4 Transcription Factor; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D016875:tau Proteins; C063261:acetylleucyl-leucyl-norleucinal; D051705:Sp3 Transcription Factor