A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzheimer's disease.
Among the earliest invariant neuropathological changes in Alzheimer's disease (AD) is the degeneration of vulnerable hippocampal CA1 and subicular pyramidal neurons. Semaphorin 3A (Sema3A) is a secreted protein that functions in signaling growth cone collapse, chemorepulsion and neuronal apoptosis during early development of the central nervous system. In this report we show that accumulation of an internalized form of Sema3A is associated with degeneration of neurons in vulnerable fields of the hippocampus during AD. Accumulation of Sema3A overlaps the appearance of phosphorylated MAP1B and tau in many neurons, suggesting that Sema3A signaling at some level may be coupled to these previously identified cytoskeletal markers of neurodegeneration. Consistent with this, we isolated and partially characterized a multiprotein complex from the hippocampus of patients with AD that contains phosphorylated MAP1B, collapsin-response mediator protein 2 (CRMP-2), Plexins A1 and A2, and a processed form of Sema3A. A model is presented in which aberrant release of Sema3A from expressing neurons in the subiculum during AD results in the internalization and transport of Sema3A from this field to CA1. Within the context of the myriad of potential insults that contribute to Alzheimer's and other neurodegenerative diseases, the bioactivity of Sema3A may contribute either directly to neurodegeneration by inducing neuronal collapse, or indirectly by abrogating the recovery capabilities of adult neurons faced with these insults.
Department of Pathology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Paul F
PF
Good
Daisy
D
Alapat
Amy
A
Hsu
Caryn
C
Chu
Daniel
D
Perl
Xiaping
X
Wen
David E
DE
Burstein
D Stave
DS
Kohtz
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D000939:Epitopes; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D046911:Macromolecular Substances / Q000737:chemistry / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000378:metabolism; D040121:Semaphorin-3A / Q000378:metabolism*; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism
D015415:Biomarkers; D000939:Epitopes; D036341:Intercellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C492116:PLXNA1 protein, human; D011956:Receptors, Cell Surface; D040121:Semaphorin-3A; C095114:collapsin response mediator protein-2; C085284:microtubule-associated protein 1B; D016875:tau Proteins