Coexisting Cholinergic and Parahippocampal Degeneration: A Key to Memory Loss in Dementia and a Challenge for Transgenic Models?

Vol. 5, No. 5, 2008

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Modeling Neurodegenerative Disease in vivo

Coexisting Cholinergic and Parahippocampal Degeneration: A Key to Memory Loss in Dementia and a Challenge for Transgenic Models?
Jean-Christophe Cassel^a, Chantal Mathis^a, Monique Majchrzak^a, Pierre-Henri Moreau^a, John C. Dalrymple-Alford^b

^aLINC UMR 7191, Université Louis Pasteur, CNRS, Institut Fédératif de Recherche IFR 37, GDR CNRS 2905, Strasbourg, France,
^bVan der Veer Institute for Parkinson's and Brain Research, and Department of Psychology, University of Canterbury, Christchurch, New Zealand

Address of Corresponding Author

Neurodegenerative Dis 2008;5:304-317 (DOI: 10.1159/000135615)

Key Words

Alzheimer's disease
Lesion models
Cholinergic basal forebrain
Entorhinal cortex
Memory
Transgenic models

Abstract

One century after Alzheimer's initial report, a variety of animal models of Alzheimer's disease (AD) are being used to mimic one or more pathological signs viewed as critical for the evolution of cognitive decline in dementia. Among the most common are, (a) traditional lesion models aimed at reproducing the degeneration of one of two key brain regions affected in AD, namely the cholinergic basal forebrain (CBF) and the transentorhinal region, and (b) transgenic mouse models aimed at reproducing AD histopathological hallmarks, namely amyloid plaques and neurofibrillary tangles. These models have provided valuable insights into the development and consequences of the pathology, but they have not consistently reproduced the severity of memory deficits exhibited in AD. The reasons for this lack of correspondence with the severity of expected deficits may include the limited replication of multiple neuropathology in potentially key brain regions. A recent lesion model in the rat found that severe memory impairment was obtained only when the two traditional lesions were combined together (i.e. conjoint CBF and entorhinal cortex lesions), indicative of a dramatic impact on cognitive function when there is coexisting, rather than isolated, damage in these two brain regions. It is proposed that combining AD transgenic mouse models with additional experimental damage to both the CBF and entorhinal regions might provide a unique opportunity to further understand the evolution of the disease and improve treatments of severe cognitive dysfunction in neurodegenerative dementias.

References

1.: Alzheimer A: Über eine eigenartige Erkrankung der Hirnrinde. Allg Zschr Psychiatr Psychisch Gerichtl Mediz 1907;64:146-148.
2.: Hardy J: The relationship between amyloid and tau. J Mol Neurosci 2003;20:203-206.
3.: Monaco S, Zanusso G, Mazzucco S, Rizzuto N: Cerebral amyloidoses: molecular pathways and therapeutic challenges. Curr Med Chem 2006;13:1903-1913.
4.: Fleischman DA, Gabrieli J: Long-term memory in Alzheimer's disease. Curr Opin Neurobiol 1999;9:240-244.
5.: Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J: The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 2004;62:1984-1989.
6.: Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R: Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;30:572-580.
7.: Bowen DM, Smith CB, White P, Davison AN: Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 1976;99:459-496.
8.: Davies P, Maloney AJ: Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet 1976;2:1403.
9.: Perry EK, Perry RH, Blessed G, Tomlinson BE: Changes in brain cholinesterases in senile dementia of Alzheimer type. Neuropathol Appl Neurobiol 1978;4:273-277.
10.: Baskin DS, Browning JL, Pirozzolo FJ, Korporaal S, Baskin JA, Appel SH: Brain choline acetyltransferase and mental function in Alzheimer disease. Arch Neurol 1999;56:1121-1123.
11.: Frolich L: The cholinergic pathology in Alzheimer's disease - discrepancies between clinical experience and pathophysiological findings. J Neural Transm 2002;109:1003-1013.
12.: Minger SL, Esiri MM, McDonald B, Keene J, Carter J, Hope T, Francis PT: Cholinergic deficits contribute to behavioral disturbance in patients with dementia. Neurology 2000;55:1460-1467.
13.: Pappas BA, Bayley PJ, Bui BK, Hansen LA, Thal LJ: Choline acetyltransferase activity and cognitive domain scores of Alzheimer's patients. Neurobiol Aging 2000;21:11-17.
14.: Terry AV Jr, Buccafusco JJ: The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 2003;306:821-827.
15.: Mesulam M: The cholinergic lesion of Alzheimer's disease: pivotal factor or side show? Learn Mem 2004;11:43-49.
16.: Parent MB, Baxter MG: Septohippocampal acetylcholine: involved in but not necessary for learning and memory? Learn Mem 2004;11:9-20.
17.: Bartus RT, Dean RL III, Beer B, Lippa AS: The cholinergic hypothesis of geriatric memory dysfunction. Science 1982;217:408-414.
18.: Knopman DS, Boeve BF, Petersen RC: Essentials of the proper diagnoses of mild cognitive impairment, dementia, and major subtypes of dementia. Mayo Clin Proc 2003;78:1290-1308.
19.: Kaufer DI: Pharmacologic therapy of dementia with Lewy bodies. J Geriatr Psychiatry Neurol 2002;15:224-232.
20.: Lleo A, Greenberg SM, Growdon JH: Current pharmacotherapy for Alzheimer's disease. Annu Rev Med 2006;57:513-533.
21.: Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P: Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-2115.
22.: Doody RS, Stevens JC, Beck C, Dubinsky RM, Kaye JA, Gwyther L, Mohs RC, Thal LJ, Whitehouse PJ, DeKosky ST, Cummings JL: Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1154-1166.
23.: Davis KL, Mohs RC, Marin D, Purohit DP, Perl DP, Lantz M, Austin G, Haroutunian V: Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA 1999;281:1401-1406.
24.: Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M: Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau. Nat Neurosci 1998;1:355-358.
25.: Van Dam D, D'Hooge R, Staufenbiel M, Van Ginneken C, Van Meir F, De Deyn PP: Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. Eur J Neurosci 2003;17:388-396.
26.: DeKosky ST, Ikonomovic MD, Styren SD, Beckett L, Wisniewski S, Bennett DA, Cochran EJ, Kordower JH, Mufson EJ: Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 2002;51:145-155.
27.: Braak H, Braak E: Entorhinal-hippocampal interaction in mnestic disorders. Hippocampus 1993;3:239-246.
28.: Apostolova LG, Dutton RA, Dinov ID, Hayashi KM, Toga AW, Cummings JL, Thompson PM: Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps. Arch Neurol 2006;63:693-699.
29.: Bell-McGinty S, Lopez OL, Meltzer CC, Scanlon JM, Whyte EM, Dekosky ST, Becker JT: Differential cortical atrophy in subgroups of mild cognitive impairment. Arch Neurol 2005;62:1393-1397.
30.: Hirao K, Ohnishi T, Matsuda H, Nemoto K, Hirata Y, Yamashita F, Asada T, Iwamoto T: Functional interactions between entorhinal cortex and posterior cingulate cortex at the very early stage of Alzheimer's disease using brain perfusion single-photon emission computed tomography. Nucl Med Commun 2006;27:151-156.
31.: Masdeu JC, Zubieta JL, Arbizu J: Neuroimaging as a marker of the onset and progression of Alzheimer's disease. J Neurol Sci 2005;236:55-64.
32.: Rodrigue KM, Raz N: Shrinkage of the entorhinal cortex over five years predicts memory performance in healthy adults. J Neurosci 2004;24:956-963.
33.: Stoub TR, Bulgakova M, Leurgans S, Bennett DA, Fleischman D, Turner DA, deToledo-Morrell L: MRI predictors of risk of incident Alzheimer disease: a longitudinal study. Neurology 2005;64:1520-1524.
34.: Whitwell JL, Przybelski SA, Weigand SD, Knopman DS, Boeve BF, Petersen RC, Jack CR Jr: 3D maps from multiple MRI illustrate changing atrophy patterns as subjects progress from mild cognitive impairment to Alzheimer's disease. Brain 2007;130:1777-1786.
35.: Stoub TR, deToledo-Morrell L, Stebbins GT, Leurgans S, Bennett DA, Shah RC: Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer's disease. Proc Natl Acad Sci USA 2006;103:10041-10045.
36.: Nestor PJ, Fryer TD, Hodges JR: Declarative memory impairments in Alzheimer's disease and semantic dementia. Neuroimage 2006;30:1010-1020.
37.: LaFerla FM, Oddo S: Alzheimer's disease: Abeta, tau and synaptic dysfunction. Trends Mol Med 2005;11:170-176.
38.: McGowan E, Eriksen J, Hutton M: A decade of modeling Alzheimer's disease in transgenic mice. Trends Genet 2006;22:281-289.
39.: Spires TL, Hyman BT: Transgenic models of Alzheimer's disease: learning from animals. NeuroRx 2005;2:423-437.
40.: Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM: Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron 2005;45:675-688.
41.: Dodart JC, Mathis C, Bales KR, Paul SM: Does my mouse have Alzheimer's disease? Genes Brain Behav 2002;1:142-155.
42.: Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L: Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc Natl Acad Sci USA 1999;96:3228-3233.
43.: Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E: Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001;293:1487-1491.
44.: Ohno M, Sametsky EA, Younkin LH, Oakley H, Younkin SG, Citron M, Vassar R, Disterhoft JF: BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron 2004;41:27-33.
45.: German DC, Eisch AJ: Mouse models of Alzheimer's disease: insight into treatment. Rev Neurosci 2004;15:353-369.
46.: Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B: Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 1997;94:13287-13292.
47.: Phinney AL, Deller T, Stalder M, Calhoun ME, Frotscher M, Sommer B, Staufenbiel M, Jucker M: Cerebral amyloid induces aberrant axonal sprouting and ectopic terminal formation in amyloid precursor protein transgenic mice. J Neurosci 1999;19:8552-8559.
48.: Roder S, Danober L, Pozza MF, Lingenhoehl K, Wiederhold KH, Olpe HR: Electrophysiological studies on the hippocampus and prefrontal cortex assessing the effects of amyloidosis in amyloid precursor protein 23 transgenic mice. Neuroscience 2003;120:705-720.
49.: Boncristiano S, Calhoun ME, Howard V, Bondolfi L, Kaeser SA, Wiederhold KH, Staufenbiel M, Jucker M: Neocortical synaptic bouton number is maintained despite robust amyloid deposition in APP23 transgenic mice. Neurobiol Aging 2005;26:607-613.
50.: Boncristiano S, Calhoun ME, Kelly PH, Pfeifer M, Bondolfi L, Stalder M, Phinney AL, Abramowski D, Sturchler-Pierrat C, Enz A, Sommer B, Staufenbiel M, Jucker M: Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis. J Neurosci 2002;22:3234-3243.
51.: Van Dam D, Marescau B, Engelborghs S, Cremers T, Mulder J, Staufenbiel M, De Deyn PP: Analysis of cholinergic markers, biogenic amines, and amino acids in the CNS of two APP overexpression mouse models. Neurochem Int 2005;46:409-422.
52.: Bondolfi L, Calhoun M, Ermini F, Kuhn HG, Wiederhold KH, Walker L, Staufenbiel M, Jucker M: Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice. J Neurosci 2002;22:515-522.
53.: Calhoun ME, Wiederhold KH, Abramowski D, Phinney AL, Probst A, Sturchler-Pierrat C, Staufenbiel M, Sommer B, Jucker M: Neuron loss in APP transgenic mice. Nature 1998;395:755-756.
54.: Kelly PH, Bondolfi L, Hunziker D, Schlecht HP, Carver K, Maguire E, Abramowski D, Wiederhold KH, Sturchler-Pierrat C, Jucker M, Bergmann R, Staufenbiel M, Sommer B: Progressive age-related impairment of cognitive behavior in APP23 transgenic mice. Neurobiol Aging 2003;24:365-378.
55.: Van Dam D, D'Hooge R, Staufenbiel M, Van Ginneken C, Van Meir F, De Deyn PP: Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. Eur J Neurosci 2003;17:388-396.
56.: Van Dam D, Abramowski D, Staufenbiel M, De Deyn PP: Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model. Psychopharmacology (Berl) 2005;180:177-190.
57.: Vloeberghs E, Van Dam D, D'Hooge R, Staufenbiel M, De Deyn PP: APP23 mice display working memory impairment in the plus-shaped water maze. Neurosci Lett 2006;407:6-10.
58.: Hellweg R, Lohmann P, Huber R, Kuhl A, Riepe MW: Spatial navigation in complex and radial mazes in APP23 animals and neurotrophin signaling as a biological marker of early impairment. Learn Mem 2006;13:63-71.
59.: Prut L, Abramowski D, Krucker T, Levy CL, Roberts AJ, Staufenbiel M, Wiessner C: Aged APP23 mice show a delay in switching to the use of a strategy in the Barnes maze. Behav Brain Res 2007;179:107-110.
60.: Hartman RE, Izumi Y, Bales KR, Paul SM, Wozniak DF, Holtzman DM: Treatment with an amyloid-beta antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer's disease. J Neurosci 2005;25:6213-6220.
61.: Irizarry MC, Soriano F, Mcnamara M, Page KJ, Schenk D, Games D, Hyman BT: Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci 1997;17:7053-7059.
62.: Masliah E, Sisk A, Mallory M, Games D: Neurofibrillary pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. J Neuropathol Exp Neurol 2001;60:357-368.
63.: Reilly JF, Games D, Rydel RE, Freedman S, Schenk D, Young WG, Morrison JH, Bloom FE: Amyloid deposition in the hippocampus and entorhinal cortex: quantitative analysis of a transgenic mouse model. Proc Natl Acad Sci USA 2003;100:4837-4842.
64.: Dodart JC, Meziane H, Mathis C, Bales KR, Paul SM, Ungerer A: Behavioral disturbances in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Behav Neurosci 1999;113:982-990.
65.: Dodart JC, Mathis C, Saura J, Bales KR, Paul SM, Ungerer A: Neuroanatomical abnormalities in behaviorally characterized APP(V717F) transgenic mice. Neurobiol Dis 2000;7:71-85.
66.: Gonzalez-Lima F, Berndt JD, Valla JE, Games D, Reiman EM: Reduced corpus callosum, fornix and hippocampus in PDAPP transgenic mouse model of Alzheimer's disease. Neuroreport 2001;12:2375-2379.
67.: Valla J, Schneider LE, Gonzalez-Lima F, Reiman EM: Nonprogressive transgene-related callosal and hippocampal changes in PDAPP mice. Neuroreport 2006;17:829-832.
68.: Redwine JM, Kosofsky B, Jacobs RE, Games D, Reilly JF, Morrison JH, Young WG, Bloom FE: Dentate gyrus volume is reduced before onset of plaque formation in PDAPP mice: a magnetic resonance microscopy and stereologic analysis. Proc Natl Acad Sci USA 2003;100:1381-1386.
69.: Weiss C, Venkatasubramanian PN, Aguado AS, Power JM, Tom BC, Li L, Chen KS, Disterhoft JF, Wyrwicz AM: Impaired eyeblink conditioning and decreased hippocampal volume in PDAPP V717F mice. Neurobiol Dis 2002;11:425-433.
70.: Lanz TA, Carter DB, Merchant KM: Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype. Neurobiol Dis 2003;13:246-253.
71.: German DC, Nelson O, Liang F, Liang CL, Games D: The PDAPP mouse model of Alzheimer's disease: locus coeruleus neuronal shrinkage. J Comp Neurol 2005;492:469-476.
72.: Donovan MH, Yazdani U, Norris RD, Games D, German DC, Eisch AJ: Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease. J Comp Neurol 2006;495:70-83.
73.: German DC, Yazdani U, Speciale SG, Pasbakhsh P, Games D, Liang CL: Cholinergic neuropathology in a mouse model of Alzheimer's disease. J Comp Neurol 2003;462:371-381.
74.: Bales KR, Tzavara ET, Wu S, Wade MR, Bymaster FP, Paul SM, Nomikos GG: Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A beta antibody. J Clin Invest 2006;116:825-832.
75.: Su Y, Ni B: Selective deposition of amyloid-beta protein in the entorhinal-dentate projection of a transgenic mouse model of Alzheimer's disease. J Neurosci Res 1998;53:177-186.
76.: Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM: Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci 2002;5:452-457.
77.: Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L, Games D, Freedman SB, Morris RG: A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature 2000;408:975-979.
78.: Brody DL, Holtzman DM: Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury. Exp Neurol 2006;197:330-340.
79.: Huitron-Resendiz S, Sanchez-Alavez M, Gallegos R, Berg G, Crawford E, Giacchino JL, Games D, Henriksen SJ, Criado JR: Age-independent and age-related deficits in visuospatial learning, sleep-wake states, thermoregulation and motor activity in PDAPP mice. Brain Res 2002;928:126-137.
80.: Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH: A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006;440:352-357.
81.: Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G: Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996;274:99-102.
82.: Tomidokoro Y, Harigaya Y, Matsubara E, Ikeda M, Kawarabayashi T, Shirao T, Ishiguro K, Okamoto K, Younkin SG, Shoji M: Brain Abeta amyloidosis in APPsw mice induces accumulation of presenilin-1 and tau. J Pathol 2001;194:500-506.
83.: Dong H, Martin MV, Chambers S, Csernansky JG: Spatial relationship between synapse loss and beta-amyloid deposition in Tg2576 mice. J Comp Neurol 2007;500:311-321.
84.: Hu L, Wong TP, Cote SL, Bell KF, Cuello AC: The impact of Abeta-plaques on cortical cholinergic and non-cholinergic presynaptic boutons in Alzheimer's disease-like transgenic mice. Neuroscience 2003;121:421-432.
85.: Wong TP, Debeir T, Duff K, Cuello AC: Reorganization of cholinergic terminals in the cerebral cortex and hippocampus in transgenic mice carrying mutated presenilin-1 and amyloid precursor protein transgenes. J Neurosci 1999;19:2706-2716.
86.: Wenk GL, McGann-Gramling K, Hauss-Wegrzyniak B: The presence of the APP(swe) mutation in mice does not increase the vulnerability of cholinergic basal forebrain neurons to neuroinflammation. Neuroscience 2004;125:769-776.
87.: Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE: Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 2006;103:5161-5166.
88.: Gau JT, Steinhilb ML, Kao TC, D'Amato CJ, Gaut JR, Frey KA, Turner RS: Stable beta-secretase activity and presynaptic cholinergic markers during progressive central nervous system amyloidogenesis in Tg2576 mice. Am J Pathol 2002;160:731-738.
89.: Apelt J, Kumar A, Schliebs R: Impairment of cholinergic neurotransmission in adult and aged transgenic Tg2576 mouse brain expressing the Swedish mutation of human beta-amyloid precursor protein. Brain Res 2002;953:17-30.
90.: Klingner M, Apelt J, Kumar A, Sorger D, Sabri O, Steinbach J, Scheunemann M, Schliebs R: Alterations in cholinergic and non-cholinergic neurotransmitter receptor densities in transgenic Tg2576 mouse brain with beta-amyloid plaque pathology. Int J Dev Neurosci 2003;21:357-369.
91.: Luth HJ, Apelt J, Ihunwo AO, Arendt T, Schliebs R: Degeneration of beta-amyloid-associated cholinergic structures in transgenic APP SW mice. Brain Res 2003;977:16-22.
92.: Zhang B, Veasey SC, Wood MA, Leng LZ, Kaminski C, Leight S, Abel T, Lee VM, Trojanowski JQ: Impaired rapid eye movement sleep in the Tg2576 APP murine model of Alzheimer's disease with injury to pedunculopontine cholinergic neurons. Am J Pathol 2005;167:1361-1369.
93.: Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH: The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. J Neurosci 2002;22:1858-1867.
94.: Arendash GW, Lewis J, Leighty RE, McGowan E, Cracchiolo JR, Hutton M, Garcia MF: Multi-metric behavioral comparison of APPsw and P301L models for Alzheimer's disease: linkage of poorer cognitive performance to tau pathology in forebrain. Brain Res 2004;1012:29-41.
95.: Zhuo JM, Prescott SL, Murray ME, Zhang HY, Baxter MG, Nicolle MM: Early discrimination reversal learning impairment and preserved spatial learning in a longitudinal study of Tg2576 APPsw mice. Neurobiol Aging 2007;28:1248-1257.
96.: King DL, Arendash GW, Crawford F, Sterk T, Menendez J, Mullan MJ: Progressive and gender-dependent cognitive impairment in the APP(SW) transgenic mouse model for Alzheimer's disease. Behav Brain Res 1999;103:145-162.
97.: Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW: A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 2000;408:982-985.
98.: Ognibene E, Middei S, Daniele S, Adriani W, Ghirardi O, Caprioli A, Laviola G: Aspects of spatial memory and behavioral disinhibition in Tg2576 transgenic mice as a model of Alzheimer's disease. Behav Brain Res 2005;156:225-232.
99.: Hale G, Good M: Impaired visuospatial recognition memory but normal object novelty detection and relative familiarity judgments in adult mice expressing the APPswe Alzheimer's disease mutation. Behav Neurosci 2005;119:884-891.
100.: Barnes P, Good M: Impaired Pavlovian cued fear conditioning in Tg2576 mice expressing a human mutant amyloid precursor protein gene. Behav Brain Res 2005;157:107-117.
101.: Gotz J, Chen F, Van Dorpe J, Nitsch RM: Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 2001a;293:1491-1495.
102.: Ishihara T, Zhang B, Higuchi M, Yoshiyama Y, Trojanowski JQ, Lee VM: Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice. Am J Pathol 2001;158:555-562.
103.: Murakami T, Paitel E, Kawarabayashi T, Ikeda M, Chishti MA, Janus C, Matsubara E, Sasaki A, Kawarai T, Phinney AL, Harigaya Y, Horne P, Egashira N, Mishima K, Hanna A, Yang J, Iwasaki K, Takahashi M, Fujiwara M, Ishiguro K, Bergeron C, Carlson GA, Abe K, Westaway D, George-Hyslop P, Shoji M: Cortical neuronal and glial pathology in TgTauP301L transgenic mice: neuronal degeneration, memory disturbance, and phenotypic variation. Am J Pathol 2006;169:1365-1375.
104.: Pennanen L, Welzl H, D'Adamo P, Nitsch RM, Gotz J: Accelerated extinction of conditioned taste aversion in P301L tau transgenic mice. Neurobiol Dis 2004;15:500-509.
105.: Gotz J, Chen F, Barmettler R, Nitsch RM: Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 2001b; 276:529-534.
106.: Ramsden M, Kotilinek L, Forster C, Paulson J, McGowan E, SantaCruz K, Guimaraes A, Yue M, Lewis J, Carlson G, Hutton M, Ashe KH: Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci 2005;25:10637-10647.
107.: Lin WL, Lewis J, Yen SH, Hutton M, Dickson DW: Filamentous tau in oligodendrocytes and astrocytes of transgenic mice expressing the human tau isoform with the P301L mutation. Am J Pathol 2003;162:213-218.
108.: Berger Z, Roder H, Hanna A, Carlson A, Rangachari V, Yue M, Wszolek Z, Ashe K, Knight J, Dickson D, Andorfer C, Rosenberry TL, Lewis J, Hutton M, Janus C: Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 2007;27:3650-3662.
109.: Pennanen L, Wolfer DP, Nitsch RM, Gotz J: Impaired spatial reference memory and increased exploratory behavior in P301L tau transgenic mice. Genes Brain Behav 2006;5:369-379.
110.: Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM: Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci 2007;27:9115-9129.
111.: McGowan E, Sanders S, Iwatsubo T, Takeuchi A, Saido T, Zehr C, Yu X, Uljon S, Wang R, Mann D, Dickson D, Duff K: Amyloid phenotype characterization of transgenic mice overexpressing both mutant amyloid precursor protein and mutant presenilin 1 transgenes. Neurobiol Dis 1999;6:231-244.
112.: Takeuchi A, Irizarry MC, Duff K, Saido TC, Hsiao AK, Hasegawa M, Mann DM, Hyman BT, Iwatsubo T: Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss. Am J Pathol 2000;157:331-339.
113.: Urbanc B, Cruz L, Le R, Sanders J, Ashe KH, Duff K, Stanley HE, Irizarry MC, Hyman BT: Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease. Proc Natl Acad Sci USA 2002;99:13990-13995.
114.: Hernandez D, Sugaya K, Qu T, McGowan E, Duff K, McKinney M: Survival and plasticity of basal forebrain cholinergic systems in mice transgenic for presenilin-1 and amyloid precursor protein mutant genes. Neuroreport 2001;12:1377-1384.
115.: Dickey CA, Loring JF, Montgomery J, Gordon MN, Eastman PS, Morgan D: Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice. J Neurosci 2003;23:5219-5226.
116.: Sadowski M, Pankiewicz J, Scholtzova H, Ji Y, Quartermain D, Jensen CH, Duff K, Nixon RA, Gruen RJ, Wisniewski T: Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice. J Neuropathol Exp Neurol 2004;63:418-428.
117.: Gureviciene I, Ikonen S, Gurevicius K, Sarkaki A, van Groen T, Pussinen R, Ylinen A, Tanila H: Normal induction but accelerated decay of LTP in APP + PS1 transgenic mice. Neurobiol Dis 2004;15:188-195.
118.: Trinchese F, Liu S, Battaglia F, Walter S, Mathews PM, Arancio O: Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice. Ann Neurol 2004;55:801-814.
119.: Arendash GW, King DL, Gordon MN, Morgan D, Hatcher JM, Hope CE, Diamond DM: Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes. Brain Res 2001;891:42-53.
120.: Todd RJ, Volmar CH, Dwivedi S, Town T, Crescentini R, Crawford F, Tan J, Mullan M: Behavioral effects of CD40-CD40L pathway disruption in aged PSAPP mice. Brain Res 2004;1015:161-168.
121.: Puolivali J, Wang J, Heikkinen T, Heikkila M, Tapiola T, van Groen T, Tanila H: Hippocampal A beta 42 levels correlate with spatial memory deficit in APP and PS1 double transgenic mice. Neurobiol Dis 2002;9:339-347.
122.: Jensen MT, Mottin MD, Cracchiolo JR, Leighty RE, Arendash GW: Lifelong immunization with human beta-amyloid (1-42) protects Alzheimer's transgenic mice against cognitive impairment throughout aging. Neuroscience 2005;130:667-684.
123.: Liu L, Tapiola T, Herukka SK, Heikkila M, Tanila H: Abeta levels in serum, CSF and brain, and cognitive deficits in APP + PS1 transgenic mice. Neuroreport 2003;14:163-166.
124.: Gordon MN, King DL, Diamond DM, Jantzen PT, Boyett KV, Hope CE, Hatcher JM, DiCarlo G, Gottschall WP, Morgan D, Arendash GW: Correlation between cognitive deficits and Abeta deposits in transgenic APP+PS1 mice. Neurobiol Aging 2001;22:377-385.
125.: Ribe EM, Perez M, Puig B, Gich I, Lim F, Cuadrado M, Sesma T, Catena S, Sanchez B, Nieto M, Gomez-Ramos P, Moran MA, Cabodevilla F, Samaranch L, Ortiz L, Perez A, Ferrer I, Avila J, Gomez-Isla T: Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol Dis 2005;20:814-822.
126.: Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM: Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging 2003a;24:1063-1070.
127.: Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM: Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003b;39:409-421.
128.: Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL, LaFerla FM: Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem 2006;281:1599-1604.
129.: Chin J, Massaro CM, Palop JJ, Thwin MT, Yu GQ, Bien-Ly N, Bender A, Mucke L: Reelin depletion in the entorhinal cortex of human amyloid precursor protein transgenic mice and humans with Alzheimer's disease. J Neurosci 2007;27:2727-2733.
130.: Janelsins MC, Mastrangelo MA, Oddo S, LaFerla FM, Federoff HJ, Bowers WJ: Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice. J Neuroinflammation 2005;2:23.
131.: Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A, LaFerla FM: M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 2006;49:671-682.
132.: Billings LM, Green KN, McGaugh JL, LaFerla FM: Learning decreases A beta*56 and tau pathology and ameliorates behavioral decline in 3xTg-AD mice. J Neurosci 2007;27:751-761.
133.: Clinton LK, Billings LM, Green KN, Caccamo A, Ngo J, Oddo S, McGaugh JL, LaFerla FM: Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice. Neurobiol Dis 2007;28:76-82.
134.: Oddo S, Vasilevko V, Caccamo A, Kitazawa M, Cribbs DH, LaFerla FM: Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. J Biol Chem 2006;281:39413-39423.
135.: Caccamo A, Oddo S, Tran LX, LaFerla FM: Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. Am J Pathol 2007;170:1669-1675.
136.: Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L, Games D, Freedman SB, Morris RG: A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature 2000;408:975-979.
137.: Ashe KH: Learning and memory in transgenic mice modeling Alzheimer's disease. Learn Mem 2001;8:301-308.
138.: Savonenko A, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong MP, Price DL, Tang F, Markowska AL, Borchelt DR: Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis 2005;18:602-617.
139.: Aggleton JP, Pearce JM: Neural systems underlying episodic memory: insights from animal research. Philos Trans R Soc Lond B Biol Sci 2001;356:1467-1482.
140.: Hernandez D, Sugaya K, Qu T, McGowan E, Duff K, McKinney M: Survival and plasticity of basal forebrain cholinergic systems in mice transgenic for presenilin-1 and amyloid precursor protein mutant genes. Neuroreport 2001;12:1377-1384.
141.: Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I, Mueller R, Morgan D, Sanders S, Zehr C, O'Campo K, Hardy J, Prada CM, Eckman C, Younkin S, Hsiao K, Duff K: Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998;4:97-100.
142.: Bronfman FC, Moechars D, Van Leuven F: Acetylcholinesterase-positive fiber deafferentation and cell shrinkage in the septohippocampal pathway of aged amyloid precursor protein London mutant transgenic mice. Neurobiol Dis 2000;7:152-168.
143.: Dodart JC, Mathis C, Bales KR, Paul SM, Ungerer A: Early regional cerebral glucose hypometabolism in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Neurosci Lett 1999;277:49-52.
144.: Descarries L, Aznavour N, Hamel E: The acetylcholine innervation of cerebral cortex: new data on its normal development and its fate in the hAPP(SW,IND) mouse model of Alzheimer's disease. J Neural Transm 2005;112:149-162.
145.: Sarter M, Bruno JP, Givens B: Attentional functions of cortical cholinergic inputs: what does it mean for learning and memory? Neurobiol Learn Mem 2003;80:245-256.
146.: Wenk GL: The nucleus basalis magnocellularis cholinergic system: one hundred years of progress. Neurobiol Learn Memory 1997;67:85-95.
147.: Lehmann O, Grottick AJ, Cassel JC, Higgins GA: A double dissociation between serial reaction time and radial maze performance in rats subjected to 192 IgG-saporin lesions of the nucleus basalis and/or the septal region. Eur J Neurosci 2003;18:651-666.
148.: Steffenach HA, Witter M, Moser MB, Moser EI: Spatial memory in the rat requires the dorsolateral band of the entorhinal cortex. Neuron 2005;45:301-313.
149.: Aggleton J: Identifying cortical inputs to the rat hippocampus that subserve allocentric spatial processes: a simple problem with a complex answer. Hippocampus 2000;10:466-474.
150.: Tiraboschi P, Hansen LA, Alford M, Sabbagh MN, Schoos B, Masliah E, Thal LJ, Corey-Bloom J: Cholinergic dysfunction in diseases with Lewy bodies. Neurology 2000;54:407-411.
151.: Traissard N, Herbeaux K, Cosquer B, Jeltsch H, Ferry B, Galani R, Pernon A, Majchrzak M, Cassel JC: Combined damage to entorhinal cortex and cholinergic basal forebrain neurons, two early neurodegenerative features accompanying Alzheimer's disease: effects on locomotor activity and memory functions in rats. Neuropsychopharmacology 2007;32:851-871.
152.: Baxter MG: Effects of selective immunotoxic lesions on learning and memory. Meth Mol Biol 2001;166:249-265.
153.: Wrenn CC, Wiley RG: The behavioral functions of the cholinergic basal forebrain: lessons from 192 igg-saporin. Int J Dev Neurosci 1998;16:595-602.
154.: Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA: Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 2005;25:7709-7717.
155.: Celone KA, Calhoun VD, Dickerson BC, Atri A, Chua EF, Miller SL, DePeau K, Rentz DM, Selkoe DJ, Blacker D, Albert MS, Sperling RA: Alterations in memory networks in mild cognitive impairment and Alzheimer's disease: an independent component analysis. J Neurosci 2006;26:10222-10231.
156.: Thal JJ, Mandel RJ, Terry RD, Buzsaki, Gage FH: Nucleus basalis lesions fail to induce senile plaques in the rat. Exp Neurol 1990;108:88-90.
157.: Ramirez MJ, Heslop KE, Francis PT, Rattray M: Expression of amyloid precursor protein, tau and presenilin RNAs in rat hippocampus following deafferentation lesions. Brain Res 2001;907:222-232.
158.: Beach TG, Potter PE, Kuo YM, Emmerling MR, Durham RA, Webster SD, Walker DG, Sue LI, Scott S, Layne KJ, Roher AE: Cholinergic deafferentation of the rabbit cortex: a new animal model of Abeta deposition. Neurosci Lett 2000;283:9-12.
159.: Folkesson R, Malkiewicz K, Kloskowska E, Nilsson T, Popova E, Bogdanovic N, Ganten U, Ganten D, Bader M, Winblad B, Benedikz E: A transgenic rat expressing human APP with the Swedish Alzheimer's disease mutation. Biochem Biophys Res Commun 2007;358:777-782.
160.: Cho YH, Jaffard R: Spatial location learning in mice with ibotenate lesions of entorhinal cortex or subiculum. Neurobiol Learn Mem 1995;64:285-290.
161.: Berger-Sweeney J, Stearns NA, Murg SL, Floerke-Nashner LR, Lappi DA, Baxter MG: Selective immunolesions of cholinergic neurons in mice: effects on neuroanatomy, neurochemistry, and behavior. J Neurosci 2001;21:8164-8173.
162.: Moreau PH, Cosquer B, Jeltsch H, Cassel JC, Mathis C: Neuroanatomical and behavioral effects of a novel version of the cholinergic immunotoxin mu p75-saporin in mice. Hippocampus, in press.
163.: Heneka MT, Ramanathan M, Jacobs AH, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T, Sastre M, Galldiks N, Zimmer A, Hoehn M, Heiss WD, Klockgether T, Staufenbiel M: Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci 2006;26:1343-1354.
164.: Chauhan NB: Cholinergic immunolesioning produced tangle-like inclusions in TgCRND8 Brain. Abstr Soc Neurosci 2006;271.8/KK9.

Author Contacts

Jean-Christophe Cassel, LINC UMR 7191 Université Louis Pasteur, CNRS
Institut Fédératif de Recherche 37, 12 rue Goethe
FR-67000 Strasbourg (France)
Tel. +33 390 241 952, Fax +33 390 241 958
E-Mail jean-christophe.cassel@linc.u-strasbg.fr

Article Information

Received: April 5, 2007
Accepted after revision: October 31, 2007
Published online: June 3, 2008
Number of Print Pages : 14
Number of Figures : 1, Number of Tables : 1, Number of References : 164

Publication Details

Neurodegenerative Diseases

Vol. 5, No. 5, Year 2008 (Cover Date: June 2008)

Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660-2854 (Print), eISSN: 1660-2862 (Online)

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	Last update: 2/6/2008