Failure of Neuronal Maturation in Alzheimer Disease Dentate Gyrus

The dentate gyrus, an important anatomic structure of the hippocampal formation, is one of the major areas in which neurogenesis takes place in the adult mammalian brain. Neurogenesis in the dentate gyrus is thought to play an important role in hippocampus-dependent learning and memory. Neurogenesis has been reported to be increased in the dentate gyrus of patients with Alzheimer disease, but it is not known whether the newly generated neurons differentiate into mature neurons. In this study, the expression of the mature neuronal marker high molecular weight microtubule-associated protein (MAP) isoforms MAP2a and b was found to be dramatically decreased in Alzheimer disease dentate gyrus, as determined by immunohistochemistry and in situ hybridization. The total MAP2, including expression of the immature neuronal marker, the MAP2c isoform, was less affected. These findings suggest that newly generated neurons in Alzheimer disease dentate gyrus do not become mature neurons, although neuroproliferation is increased.

[1]  Bin Li,et al.  Trophic factors counteract elevated FGF-2-induced inhibition of adult neurogenesis , 2007, Neurobiology of Aging.

[2]  I. Holopainen,et al.  Changes in microtubule-associated protein-2 (MAP2) expression during development and after status epilepticus in the immature rat hippocampus , 2007, International Journal of Developmental Neuroscience.

[3]  R. J. McDonald,et al.  A role for adult neurogenesis in spatial long-term memory , 2005, Neuroscience.

[4]  I. Grundke‐Iqbal,et al.  Inhibitors of protein phosphatase-2A: topography and subcellular localization. , 2004, Brain research. Molecular brain research.

[5]  I. Barajon,et al.  Circadian variations in expression of the trkB receptor in adult rat hippocampus , 2003, Brain Research.

[6]  Lin Xie,et al.  Increased hippocampal neurogenesis in Alzheimer's disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[7]  R G M Morris,et al.  Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[8]  I. Grundke‐Iqbal,et al.  The dentate gyrus neurogenesis: a therapeutic target for Alzheimer's disease , 2003, Acta Neuropathologica.

[9]  E. Gould,et al.  Neurogenesis in the adult is involved in the formation of trace memories , 2001, Nature.

[10]  C. Hock,et al.  Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. , 2000, Archives of neurology.

[11]  E. Gould,et al.  Learning enhances adult neurogenesis in the hippocampal formation , 1999, Nature Neuroscience.

[12]  F. Gage,et al.  Neurogenesis in the adult human hippocampus , 1998, Nature Medicine.

[13]  B. Shafit-Zagardo,et al.  Making sense of the multiple MAP-2 transcripts and their role in the neuron , 1998, Molecular Neurobiology.

[14]  J. Trojanowski,et al.  Editorial on Consensus Recommendations for the Postmortem Diagnosis of Alzheimer Disease from the National Institute on Aging and the Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer Disease , 1997, Journal of neuropathology and experimental neurology.

[15]  F. Gage,et al.  More hippocampal neurons in adult mice living in an enriched environment , 1997, Nature.

[16]  J. Wegiel,et al.  Relationships between Regional Neuronal Loss and Neurofibrillary Changes in the Hippocampal Formation and Duration and Severity of Alzheimer Disease , 1997, Journal of neuropathology and experimental neurology.

[17]  P. Davies,et al.  Distribution and Subcellular Localization of High‐Molecular‐Weight Microtubule‐Associated Protein‐2 Expressing Exon 8 in Brain and Spinal Cord , 1997, Journal of neurochemistry.

[18]  B. Shafit-Zagardo,et al.  Expression of Microtubule‐Associated Protein‐2a and Other Novel Microtubule‐Associated Protein‐2 Transcripts in Human Fetal Spinal Cord , 1997, Journal of neurochemistry.

[19]  C. Garner,et al.  MAP2a, an Alternatively Spliced Variant of Microtubule‐Associated Protein 2 , 1996, Journal of neurochemistry.

[20]  J. Albala,et al.  Genomic structure of human microtubule-associated protein 2 (MAP-2) and characterization of additional MAP-2 isoforms. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Tohyama,et al.  Differential expression of sgk mRNA, a member of the Ser/Thr protein kinase gene family, in rat brain after CNS injury. , 1994, Brain research. Molecular brain research.

[22]  J. Troncoso,et al.  Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease , 1994, The Lancet.

[23]  R. Buranosky,et al.  Dendritic pathology of granule cells in Alzheimer's disease is unrelated to neuritic plaques , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  S. M. Sumi,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1991, Neurology.

[25]  E. Stopa,et al.  Basic fibroblast growth factor in Alzheimer's disease. , 1990, Biochemical and biophysical research communications.

[26]  I. Fischer,et al.  Developmental Regulation of Microtubule‐Associated Protein 2 Expression in Regions of Mouse Brain , 1989, Journal of neurochemistry.

[27]  J. Nunez.  Immature and mature variants of MAP2 and tau proteins and neuronal plasticity , 1988, Trends in Neurosciences.

[28]  H. Wiśniewski,et al.  Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[29]  H. Wiśniewski,et al.  Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. , 1986, The Journal of biological chemistry.

[30]  H. Wiśniewski,et al.  MICROTUBULE ASSOCIATED PROTEIN, TAU IS A MAJOR CONSTITUENT OF ALZHEIMER PAIRED HELICAL FILAMENTS , 1986 .

[31]  A. Matus,et al.  Differential expression of distinct microtubule-associated proteins during brain development. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[32]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[33]  G. Glenner,et al.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. , 1984, Biochemical and biophysical research communications.