Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation

Familial Alzheimer disease mutations of presenilin 1 (PS-1) enhance the generation of Aβ1–42, indicating that PS-1 is involved in amyloidogenesis. However, PS-1 transgenic mice have failed to show amyloid plaques in their brains. Because PS-1 mutations facilitate apoptotic neuronal death in vitro, we did careful quantitative studies in PS-1 transgenic mice and found that neurodegeneration was significantly accelerated in mice older than 13 months (aged mice) with familial Alzheimer disease mutant PS-1, without amyloid plaque formation. However, there were significantly more neurons containing intracellularly deposited Aβ42 in aged mutant transgenic mice. Our data indicate that the pathogenic role of the PS-1 mutation is upstream of the amyloid cascade.

[1]  A. Paetau,et al.  A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1 , 1998, Nature Medicine.

[2]  B. Hyman,et al.  APPSW Transgenic Mice Develop Age‐related Aβ Deposits and Neuropil Abnormalities, but no Neuronal Loss in CA1 , 1997, Journal of neuropathology and experimental neurology.

[3]  T. Tabira,et al.  Immunohistochemical study of Alzheimer's disease using antibodies to synthetic amyloid and fibronectin , 1988, Journal of the Neurological Sciences.

[4]  D. Borchelt,et al.  Accelerated Amyloid Deposition in the Brains of Transgenic Mice Coexpressing Mutant Presenilin 1 and Amyloid Precursor Proteins , 1997, Neuron.

[5]  Takashi Asada,et al.  Familial Alzheimer's disease genes in Japanese , 1998, Journal of the Neurological Sciences.

[6]  T. Tabira,et al.  Stress induces neuronal death in the hippocampus of castrated rats , 1992, Neuroscience Letters.

[7]  Hans Clevers,et al.  Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis , 1998, Nature.

[8]  C. Haass,et al.  Proteolytic processing of Alzheimer's disease associated proteins. , 1998, Journal of neural transmission. Supplementum.

[9]  J. Hardy,et al.  The presenilins and Alzheimer's disease. , 1997, Human molecular genetics.

[10]  G. Schellenberg,et al.  Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease , 1996, Nature Medicine.

[11]  John Hardy,et al.  Amyloid, the presenilins and Alzheimer's disease , 1997, Trends in Neurosciences.

[12]  D. Pollen,et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease , 1995, Nature.

[13]  C. van Broeckhoven,et al.  Presenilin mutations in Alzheimer's disease , 1998, Human mutation.

[14]  T. Sunderland,et al.  Participation of Presenilin 2 in Apoptosis: Enhanced Basal Activity Conferred by an Alzheimer Mutation , 1996, Science.

[15]  Weiming Xia,et al.  Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice , 1997, Nature Medicine.

[16]  T. Tabira,et al.  Both N‐terminal and C‐terminal fragments of Presenilin 1 colocalize with neurofibrillary tangles in neurons and dystrophic neurites of senile plaques in Alzheimer's disease , 1998, Journal of neuroscience research.

[17]  J. Hardy,et al.  Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1 , 1996, Nature.

[18]  L. Mucke,et al.  Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein , 1995, Nature.

[19]  B. Sommer,et al.  Neuron loss in APP transgenic mice , 1998, Nature.

[20]  M. Jacquin,et al.  Neuronal and Glial Apoptosis after Traumatic Spinal Cord Injury , 1997, The Journal of Neuroscience.

[21]  T. Tabira,et al.  Decreased beta-amyloid and increased abnormal Tau deposition in the brain of aged patients with leprosy. , 1994, The American journal of pathology.

[22]  J. Hardy,et al.  Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes , 1998, Nature Medicine.

[23]  G. Buzsáki,et al.  Four modified silver methods for thick sections of formaldehyde-fixed mammalian central nervous tissue: ‘dark’ neurons, perikarya of all neurons, microglial cells and capillaries , 1993, Journal of Neuroscience Methods.

[24]  Bruce A. Yankner,et al.  Aging renders the brain vulnerable to amyloid β-protein neurotoxicity , 1998, Nature Medicine.

[25]  M. Mattson,et al.  Alzheimer’s Presenilin Mutation Sensitizes Neural Cells to Apoptosis Induced by Trophic Factor Withdrawal and Amyloid β-Peptide: Involvement of Calcium and Oxyradicals , 1997, The Journal of Neuroscience.

[26]  N. Robakis,et al.  Alzheimer's disease: a re-examination of the amyloid hypothesis , 1998, Trends in Neurosciences.

[27]  J. Buxbaum,et al.  Characterization of New Polyclonal Antibodies Specific for 40 and 42 Amino Acid-Long Amyloid β Peptides: Their Use to Examine the Cell Biology of Presenilins and the Immunohistochemistry of Sporadic Alzheimer’s Disease and Cerebral Amyloid Angiopathy Cases , 1997, Molecular medicine.

[28]  Kenneth S. Kosik,et al.  The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology , 1996, Nature Medicine.

[29]  Allan I. Levey,et al.  Familial Alzheimer's Disease–Linked Presenilin 1 Variants Elevate Aβ1–42/1–40 Ratio In Vitro and In Vivo , 1996, Neuron.