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Toxicity attributed to pre-fibrillar tau aggregates
[Copyright 2001 American Association for the Advancement of Science.]
Cholinergic neurons degenerate in tau transgenic mice in the absence of paired helical filaments/tau tangles. (From Wittmann et al., 2001.)
Primary Papers
- Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, Feany MB. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science. 2001 Jul 27;293(5530):711-4. Epub 2001 Jun 14 PubMed.
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Aβ fibrils accelerate tangle formation in mice
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[Courtesy of Juergen Goetz.]
Gallyas silver stain of neurofibrillary tangle in P301L tau transgenic mouse injected with Aβ42 fibrils.
[Courtesy of Juergen Goetz.]
Immunoelectron microscopy of twisted AT8-positive tau filaments in amygdala of P301L mice injected with Aβ42 fibrils.
Primary Papers
- 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 Aug 24;293(5534):1487-91. PubMed.
- Götz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. 2001 Aug 24;293(5534):1491-5. PubMed.
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First manipulation of an immune gene in APP transgenic mice activates microglia to clear parenchymal Aβ and shift it to blood vessels
[Courtesy of Tony Wyss-Coray.]
In the brains of APP-transgenic mice co-expressing TGF-1b (bottom row), microglia clear parenchymal amyloid deposits (green), shifting some Aβ to cerebral blood vessels (red).
Primary Papers
- Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, Masliah E, Mucke L. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med. 2001 May;7(5):612-8. PubMed.
Multiphoton microscopy through cranial window enables observation of plaque clearance by immunotherapy
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[Copyright 2001 Nature Medicine.]
Aβ deposits imaged in live, 20-month-old PDAPP mouse. (a) Red thioflavine-S staining of dense-core plaques and amyloid angiopathy on blood vessel in top left corner. (b) In vivo immunofluorescence of fibrillar and diffuse Aβ deposits (green). (c) Fluorescent angiography (blue) helps line up imaging volumes within the same animal over time. (d) Merged a−c shows plaques and amyloid angiopathy (yellow), surrounded by diffuse Aβ deposits (green).
[Copyright 2001 Nature Medicine.]
Reconstructed confocal sections taken in live mice illustrate intimate relationship of microglia (green) with Aβ (red). (a) Near injection of therapeutic anti-Aβ antibody, a marked microglial response surrounding remaining Aβ plaques was observed. (b) Much less microglial activation seen distal to the treatment site.
Primary Papers
- Bacskai BJ, Kajdasz ST, Christie RH, Carter C, Games D, Seubert P, Schenk D, Hyman BT. Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat Med. 2001 Mar;7(3):369-72. PubMed.
FDG-PET tracks normal-MCI-AD progression, becomes marker for neurodegeneration and differential diagnosis
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[Courtesy of Mony de Leon.]
First demonstration that the transition from cognitively normal to MCI to AD could be predicted from glucose metabolism in the hippocampal formation.
[Copyright 2008 J Nucl Med.]
These representative cortical 18F-FDG PET patterns of reduced neuronal metabolism across four diagnostic groups were generated by a standardized, multi-center study of 548 participants intended to support a clinical diagnosis.
Primary Papers
- de Leon MJ, Convit A, Wolf OT, Tarshish CY, DeSanti S, Rusinek H, Tsui W, Kandil E, Scherer AJ, Roche A, Imossi A, Thorn E, Bobinski M, Caraos C, Lesbre P, Schlyer D, Poirier J, Reisberg B, Fowler J. Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET). Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10966-71. Epub 2001 Aug 28 PubMed.
- Herholz K, Salmon E, Perani D, Baron JC, Holthoff V, Frölich L, Schönknecht P, Ito K, Mielke R, Kalbe E, Zündorf G, Delbeuck X, Pelati O, Anchisi D, Fazio F, Kerrouche N, Desgranges B, Eustache F, Beuthien-Baumann B, Menzel C, Schröder J, Kato T, Arahata Y, Henze M, Heiss WD. Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET. Neuroimage. 2002 Sep;17(1):302-16. PubMed.
- Mosconi L, Tsui WH, Herholz K, Pupi A, Drzezga A, Lucignani G, Reiman EM, Holthoff V, Kalbe E, Sorbi S, Diehl-Schmid J, Perneczky R, Clerici F, Caselli R, Beuthien-Baumann B, Kurz A, Minoshima S, de Leon MJ. Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer's disease, and other dementias. J Nucl Med. 2008 Mar;49(3):390-8. PubMed.
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Volumetric MRI broadly developed as marker of change over time in sporadic and familial AD
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[Courtesy of Nick Fox, UCL.]
Serial MRI scans show that, in dominantly inherited Alzheimer's disease, hippocampal volume starts shrinking at least seven years before a person's expected age of symptom onset.
[Copyright 2007 Brain.]
Atrophy in medial temporal lobe regions, including entorhinal cortex, anterior hippocampus, amygdala, in people who progressed from amnestic MCI to symptomatic Alzheimer’s dementia over three years. Surface view (top), axial, coronal, sagittal slices (bottom). (From Whitwell et al., 2007.)
[Copyright 2007 Brain.]
In the same sample, one year before symptom progression to AD dementia, gray matter atrophy has broadened. The brunt of the loss remained focused on the medial and inferior temporal lobes, although the extent and magnitude of the temporal lobe loss was greater. The amygdala, hippocampus, inferior temporal gyrus, entorhinal cortex, fusiform gyrus and the anterior temporal lobe were all involved, as well as the anterior middle temporal gyrus. Loss in the temporal lobes extended into the posterior temporal lobe, including the whole extent of the hippocampus. (From Whitwell et al., 2007.)
Primary Papers
- Dickerson BC, Goncharova I, Sullivan MP, Forchetti C, Wilson RS, Bennett DA, Beckett LA, Detoledo-Morrell L. MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer's disease. Neurobiol Aging. 2001 Sep-Oct;22(5):747-54. PubMed.
- Ridha BH, Barnes J, Bartlett JW, Godbolt A, Pepple T, Rossor MN, Fox NC. Tracking atrophy progression in familial Alzheimer's disease: a serial MRI study. Lancet Neurol. 2006 Oct;5(10):828-34. PubMed.
- Whitwell JL, Przybelski SA, Weigand SD, Knopman DS, Boeve BF, Petersen RC, Jack CR. 3D maps from multiple MRI illustrate changing atrophy patterns as subjects progress from mild cognitive impairment to Alzheimer's disease. Brain. 2007 Jul;130(Pt 7):1777-86. PubMed.
Disordered sleep emerges as risk factor
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[Copyright 2013 Sleep Research Society,]
Twenty-four-hour actigraphy recordings from two representative study participants at the 10th (top panel) and 90th (bottom panel) percentiles of sleep fragmentation. (From Lim et al., 2013.)
[Copyright 2014 American Medical Association.]
In cognitively normal middle-aged people whose sleep was monitored with polysomnography, CSF Aβ42 concentrations went up after one night of total sleep deprivation. Dotted line indicates the cutoff value of 192 pg/mL. (From Ooms et al., 2014.)
Primary Papers
- Kadotani H, Kadotani T, Young T, Peppard PE, Finn L, Colrain IM, Murphy GM, Mignot E. Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults. JAMA. 2001 Jun 13;285(22):2888-90. PubMed.
- Osorio RS, Pirraglia E, Agüera-Ortiz LF, During EH, Sacks H, Ayappa I, Walsleben J, Mooney A, Hussain A, Glodzik L, Frangione B, Martínez-Martín P, de Leon MJ. Greater risk of Alzheimer's disease in older adults with insomnia. J Am Geriatr Soc. 2011 Mar;59(3):559-62. PubMed.
- Yaffe K, Laffan AM, Harrison SL, Redline S, Spira AP, Ensrud KE, Ancoli-Israel S, Stone KL. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA. 2011 Aug 10;306(6):613-9. PubMed.
- Lim AS, Kowgier M, Yu L, Buchman AS, Bennett DA. Sleep Fragmentation and the Risk of Incident Alzheimer's Disease and Cognitive Decline in Older Persons. Sleep. 2013;36(7):1027-1032. PubMed.
- Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, Claassen JA. Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol. 2014 Aug;71(8):971-7. PubMed.
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BACE1 knockout mice are viable
Hippocampal slices of BACE1 knockout mice (B) show no microscopic differences in their morphology to controls (A). (From Roberds et al., 2001.)
Primary Papers
- Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci. 2001 Mar;4(3):233-4. PubMed.
- Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R. Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci. 2001 Mar;4(3):231-2. PubMed.
- Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum Mol Genet. 2001 Jun 1;10(12):1317-24. PubMed.
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Certain NSAIDs modulate γ-secretase to produce less Aβ42
[Copyright 2001 Macmillan Publishers Ltd.]
Treatment with sulindac sulphide, ibuprofen, and indomethacin, but not naproxen, selectively reduced Aβ42 relative to total Aβ levels. Experiments were done in Chinese hamster ovary cells (a, c, d, e), human neuroglioma cells (b), and fibroblast deficient in COX-1 and COX-2 (f), two known enzyme targets of NSAIDs.
Primary Papers
- Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, Kang DE, Marquez-Sterling N, Golde TE, Koo EH. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001 Nov 8;414(6860):212-6. PubMed.
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