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ApoE4 genotype influences timing and amount of amyloid deposition in human brain
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[Courtesy of Eric Reiman.]
Increasing distribution of PiB retention in amyloid PET study of cognitively unimpaired people at increasing risk of AD due to their ApoE genotype. From left to right: no ApoE4 allele, one ApoE4 allele, two ApoE4 alleles; right: clinical AD.
[Copyright 2009 PNAS.]
Fibrillar amyloid burden across different brain areas in cognitively normal ApoE4 non-carriers, heterozygotes, and homozygotes from a longitudinal study (white box), a homozygote carrier with recent onset of MCI, and probable AD patients from a previous study (gray box). (From Reiman et al., 2009.)
[Copyright 2010 Annals of Neurology.]
Frequency by age group for people who are "PiB-positive" among 241 cognitively normal participants, as a function their ApoE genotype. (From Morris et al., 2010.)
Primary Papers
- Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4162-7. PubMed.
- Tiraboschi P, Hansen LA, Masliah E, Alford M, Thal LJ, Corey-Bloom J. Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology. 2004 Jun 8;62(11):1977-83. PubMed.
- Sunderland T, Mirza N, Putnam KT, Linker G, Bhupali D, Durham R, Soares H, Kimmel L, Friedman D, Bergeson J, Csako G, Levy JA, Bartko JJ, Cohen RM. Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele. Biol Psychiatry. 2004 Nov 1;56(9):670-6. PubMed.
- Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J, Reeder SA, Langbaum JB, Alexander GE, Klunk WE, Mathis CA, Price JC, Aizenstein HJ, Dekosky ST, Caselli RJ. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6820-5. PubMed.
- Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, Mintun MA. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol. 2010 Jan;67(1):122-31. PubMed.
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Alzheimer's Disease Neuroimaging Initiative launched
Primary Papers
- Mueller SG, Weiner MW, Thal LJ, Petersen RC, Jack CR, Jagust W, Trojanowski JQ, Toga AW, Beckett L. Ways toward an early diagnosis in Alzheimer's disease: the Alzheimer's Disease Neuroimaging Initiative (ADNI). Alzheimers Dement. 2005 Jul;1(1):55-66. PubMed.
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AlzGene launched
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Brain ApoE levels and lipidation depend on ABCA1
[Copyright 2004 American Society for Biochemistry and Molecular Biology.]
ABCA1-deficient glia accumulate lipids. (A, B) ABCA1-/- astrocytes have more intracellular lipids than wild-type astrocytes (red droplets). (C, D) Microglia, too, show marked accumulation of lipid droplets in the absence of ABCA1 compared with wild-type cells. (From Hirsch-Reinshagen et al., 2004.)
Primary Papers
- Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem. 2004 Sep 24;279(39):40987-93. PubMed.
- Hirsch-Reinshagen V, Zhou S, Burgess BL, Bernier L, McIsaac SA, Chan JY, Tansley GH, Cohn JS, Hayden MR, Wellington CL. Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol Chem. 2004 Sep 24;279(39):41197-207. PubMed.
- Koldamova R, Staufenbiel M, Lefterov I. Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem. 2005 Dec 30;280(52):43224-35. PubMed.
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LXR pathway explored as therapeutic target
Primary Papers
- Liang Y, Lin S, Beyer TP, Zhang Y, Wu X, Bales KR, Demattos RB, May PC, Li SD, Jiang XC, Eacho PI, Cao G, Paul SM. A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes. J Neurochem. 2004 Feb;88(3):623-34. PubMed.
- Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D, Koldamova R. Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment. Mol Neurodegener. 2007;2:20. PubMed.
Chaperones regulate tau folding and aggregation
[Copyright 2004 by Oxford University Press.]
The tau chaperone CHIP is present in many neurodegenerative tauopathies, e.g., in neurofibrillary tangles and dystrophic neurites of senile plaques in AD. (A, B) Pick bodies in PiD; (C), globose tangles and tufted astrocytes in PSP; and (D, E) oligodendroglial coiled bodies and threads in CBD (F). CHIP co-localizes with tau and ubiquitin, seen in serial sections immunostained for phospho-tau (G), CHIP (H), and ubiquitin (I). CHIP staining in a PiD case (J) and pre-absorption with CHIP synthetic peptide (K). (From Petrucelli et al., 2004.)
Primary Papers
- Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A, De Lucia M, McGowan E, Lewis J, Prihar G, Kim J, Dillmann WH, Browne SE, Hall A, Voellmy R, Tsuboi Y, Dawson TM, Wolozin B, Hardy J, Hutton M. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet. 2004 Apr 1;13(7):703-14. PubMed.
Amyloid PET visualizes Aβ pathology in living human brain with Pittsburgh Compound B (PiB)
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[Courtesy of University of Pittsburgh Amyloid Imaging Group.]
First-ever PiB PET scan done in Uppsala, Sweden, on February 14, 2002.
[Courtesy of Christopher Rowe.]
Primary Papers
- Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergström M, Savitcheva I, Huang GF, Estrada S, Ausén B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Långström B. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004 Mar;55(3):306-19. PubMed.
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Default mode network activity is impaired in symptomatic and preclinical AD, overlaps with regions of amyloid
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[Copyright 2005 Society of Neuroscience.]
Convergence and hypothetical relationships across molecular, structural, and functional measures. Each image represents a projection of data onto the cortical surface of the left hemisphere. Three patterns emerge. First, regions showing default activity in young adults are highly similar to those showing amyloid deposition in older adults with AD, including both posterior cortical regions and anterior regions. Second, atrophy and metabolism disruption in AD prominently affect the posterior cortical regions also affected by amyloid deposition and less so the anterior regions. Third, the regions affected in AD and those active in default states in young adults overlap memory networks showing retrieval success effects during recognition in young adults. (From Buckner et al., 2005.)
[Copyright 2009 Neuron.]
Whole brain map shows the regions of overlap (yellow) between high amyloid burden (red) and fMRI activity (blue) differences in older people, particularly notable in the left posterior parietal cortex. (From Sperling et al., 2009.)
Primary Papers
- Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4637-42. PubMed.
- 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 Aug 24;25(34):7709-17. PubMed.
- 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 Oct 4;26(40):10222-31. PubMed.
- Sperling RA, Laviolette PS, O'keefe K, O'brien J, Rentz DM, Pihlajamaki M, Marshall G, Hyman BT, Selkoe DJ, Hedden T, Buckner RL, Becker JA, Johnson KA. Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron. 2009 Jul 30;63(2):178-88. PubMed.
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Neurovascular hypothesis articulated
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[Copyright 2004 Nature Publishing Group.]
Evoked neural events that underlie the increase in cerebral blood flow. (From Iadecola, 2004.)
[Copyright 2004 Nature Publishing Group.]
Vasoactive mediators released from neurons and glia by neural activity. (From Iadecola, 2004.)
[Copyright 2004 Nature Publishing Group.]
Local and propagated microvascular responses following activation of the somatosensory cortex. (From Iadecola, 2004.)
[Copyright 2004 Nature Publishing Group.]
Putative cellular mechanisms for the propagation of vasodilation from vessels in the activated site to the resistance arteries upstream. (From Iadecola, 2004.)
[Copyright 2004 Nature Publishing Group.]
Hypothetical time course of the interplay between vascular dysregulation, neuropathological alterations, and decline in brain function in Alzheimer's disease. (From Iadecola, 2004.)
[Copyright 1999 Nature American Inc.]
Vasodilators and vasoconstrictors affect blood flow in APP transgenic mice. (From Iadecola et al. 1999.)
Primary Papers
- Iadecola C, Zhang F, Niwa K, Eckman C, Turner SK, Fischer E, Younkin S, Borchelt DR, Hsiao KK, Carlson GA. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat Neurosci. 1999 Feb;2(2):157-61. PubMed.
- Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci. 2004 May;5(5):347-60. PubMed.
- Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 2005 Apr;28(4):202-8. PubMed.
Physical activity protects against AD
[Copyright 2016 American Medical Association.]
Consistent with findings for overall physical activity, regular walking was associated with significantly higher cognitive scores for women. (From Weuve et al., 2004.)
Primary Papers
- Abbott RD, White LR, Ross GW, Masaki KH, Curb JD, Petrovitch H. Walking and dementia in physically capable elderly men. JAMA. 2004 Sep 22;292(12):1447-53. PubMed.
- Weuve J, Kang JH, Manson JE, Breteler MM, Ware JH, Grodstein F. Physical activity, including walking, and cognitive function in older women. JAMA. 2004 Sep 22;292(12):1454-61. PubMed.
Transgenic models widely used for preclinical therapy evaluation
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[Copyright 2004 Cell Press.]
Aβ immunotherapy reduces extracellular Aβ plaques and intracellular Aβ accumulation in the 3xTg mouse model of Alzheimer's disease.
[Copyright 2004 Cell Press.]
Aβ immunotherapy in the 3xTg mouse model of Alzheimer's disease leads to the clearance of early tau pathology.
Primary Papers
- Oddo S, Billings L, Kesslak JP, Cribbs DH, Laferla FM. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron. 2004 Aug 5;43(3):321-32. PubMed.
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First transgenic rat models
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[Copyright 2013 by the Society for Neuroscience.]
This diagram illustrates regions of interest for neuronal stereological analyses in rat brain.
[Copyright 2013 by the Society for Neuroscience.]
TgF344-AD rats manifest progressive Aβ deposition. Two brain areas (cingulate cortex and hippocampus) and three age groups (6, 16, 26 months) are shown, stained for human Aβ immunohistochemistry. (From Cohen et al., 2013).
[Copyright 2013 by the Society for Neuroscience.]
TgF344-AD rats have tau hyperphosphorylation and neurofibrillary tangles. Shown here a comparison of tau pathology in AD patient, TgF344-AD rats, Tg2576 and PSAPP mice. All photomicrographs from cingulate cortex stained with MC1 antibody. (From Cohen et al.., 2013).
Primary Papers
- Echeverria V, Ducatenzeiler A, Dowd E, Jänne J, Grant SM, Szyf M, Wandosell F, Avila J, Grimm H, Dunnett SB, Hartmann T, Alhonen L, Cuello AC. Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the beta-amyloid peptide intracellularly in hippocampal and cortical neurons. Neuroscience. 2004;129(3):583-92. PubMed.
- 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 Jul 6;358(3):777-82. PubMed.
- Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, Bholat Y, Vasilevko V, Glabe CG, Breunig JJ, Rakic P, Davtyan H, Agadjanyan MG, Kepe V, Barrio JR, Bannykh S, Szekely CA, Pechnick RN, Town T. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci. 2013 Apr 10;33(15):6245-56. PubMed.
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Non-human primate models
[Copyright 2004 American Society for Investigative Pathology.]
Neuropathology of the aging vervet brain. (A) Vascular but not plaque Aβ immunoreactivity in the frontal cortex at 15 years of age (left). At 22 years, moderate numbers of Aβ42 and a few Aβ40-IR plaques in frontal cortex (middle). At 30 years, abundant Aβ42 plaques and moderate numbers of Aβ40 plaques (right). (B) Thioflavin S histological staining of abundant fibrillar plaques in frontal and temporal cortices in the 30-year-old. Vascular amyloid was prominent in temporal and occipital cortices. (From Lemere et al. 2004.)
Primary Papers
- Gandy S, Demattos RB, Lemere CA, Heppner FL, Leverone J, Aguzzi A, Ershler WB, Dai J, Fraser P, St George Hyslop P, Holtzman DM, Walker LC, Keller ET. Alzheimer's Abeta vaccination of rhesus monkeys (Macaca mulatta). Mech Ageing Dev. 2004 Feb;125(2):149-51. PubMed.
- Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Zheng JB, Seabrook TJ, Louard D, Li D, Selkoe DJ, Palmour RM, Ervin FR. Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. Am J Pathol. 2004 Jul;165(1):283-97. PubMed.
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Bigenic mice combining a core and an additional pathology
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[Copyright 2008 IOS Press.]
Greater neuronal loss in APP transgenic mice lacking nitric oxide synthase 2, which generates the neuroinflammation signaling molecule nitric oxide. (A,C,E) Hippocampi in APP tg mice; (B,D,F) same areas in APP mice without nitric oxide. Neurons were identified using NeuN immunochemistry. (From Colton et al., 2008.)
[Copyright 2008 IOS Press.]
One-year-old APP transgenic mice lacking nitric oxide (open circles) show a behavioral deficit in the radial arm water maze. (From Colton et al., 2003.)
Primary Papers
- Arancio O, Zhang HP, Chen X, Lin C, Trinchese F, Puzzo D, Liu S, Hegde A, Yan SF, Stern A, Luddy JS, Lue LF, Walker DG, Roher A, Buttini M, Mucke L, Li W, Schmidt AM, Kindy M, Hyslop PA, Stern DM, Du Yan SS. RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J. 2004 Oct 13;23(20):4096-105. PubMed.
- Colton CA, Wilcock DM, Wink DA, Davis J, Van Nostrand WE, Vitek MP. The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP. J Alzheimers Dis. 2008 Dec;15(4):571-87. PubMed.
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