Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice.
Intraneuronal alpha-synuclein (alphaSYN) inclusions constitute the hallmark lesions of a number of neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies. In a transgenic mouse model expressing mutant [A30P]alphaSYN under control of the pan-neuronal Thy1 promoter, motor impairment became significant beyond 17 months of age. Cognitive performance was measured in the Morris water maze and upon fear conditioning. At 4 months of age, transgenic mice performed like controls. However, performance in these tasks was significantly impaired in (Thy1)-h[A30P]alphaSYN mice at 12 months of age. After completion of the cognition tests, mice were sacrificed and the regional distribution of neuropathology was examined. In contrast to 4 months old animals, 12 months old transgenic mice showed alpha-synucleinopathy in several brain regions, including the central nucleus of the amygdala, which is involved in cognitive behavior of mice, and is susceptible to alphaSYN pathology in human patients. Thus, age-dependent fibrillization of alphaSYN in specific cortical regions concomitant with cognitive decline may reflect dementia with Lewy bodies in a transgenic mouse model.
Freichel
Christian
C
Pharma Research, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.
Neumann
Manuela
M
Ballard
Theresa
T
Müller
Veronika
V
Woolley
Marie
M
Ozmen
Laurence
L
Borroni
Edilio
E
Kretzschmar
Hans A
HA
Haass
Christian
C
Spooren
Will
W
Kahle
Philipp J
PJ
D000367:Age Factors; D000679:Amygdala / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal; D003072:Cognition Disorders / Q000473:pathology* / Q000503:physiopathology*; D003214:Conditioning, Classical / Q000502:physiology; D004195:Disease Models, Animal; D019286:Endopeptidase K / Q000378:metabolism; D005239:Fear; D017403:In Situ Hybridization; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology; D009460:Neurologic Examination; D011597:Psychomotor Performance; D045442:Rotarod Performance Test; D051844:alpha-Synuclein / Q000235:genetics*
D051844:alpha-Synuclein; D019286:Endopeptidase K