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Activity-dependent Aβ release linked to synaptic depression
[Image courtesy of Cell Press.]
Primary Papers
- Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R. APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37. PubMed.
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BACE cuts many substrates besides APP
[Courtesy of Christian Haass.]
This composite image based on Willem et al., 2006, shows how BACE-1 cleavage of the Type-1 membrane protein neuregulin is involved in axonal myelination.
Primary Papers
- Wong HK, Sakurai T, Oyama F, Kaneko K, Wada K, Miyazaki H, Kurosawa M, De Strooper B, Saftig P, Nukina N. beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase. J Biol Chem. 2005 Jun 17;280(24):23009-17. PubMed.
- Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, Destrooper B, Saftig P, Birchmeier C, Haass C. Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006 Oct 27;314(5799):664-6. PubMed.
- Kuhn PH, Koroniak K, Hogl S, Colombo A, Zeitschel U, Willem M, Volbracht C, Schepers U, Imhof A, Hoffmeister A, Haass C, Rossner S, Bräse S, Lichtenthaler SF. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 2012 Jul 18;31(14):3157-68. PubMed.
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Reactive astrocytes crowd near plaques, degrade Aβ
[Copyright 2003 Nature Publishing Group.]
Adult mouse astrocytes clear Aβ42 in vitro and in situ. Hippocampal brain sections of human APP-expressing mouse incubated without (g) or with (h) adult astrocytes show reduced Aβ-immunoreactive area in (h). Quantitation (i) shows less Aβ immunoreactivity in sections incubated with astrocytes than sections without astrocytes. (j) Confocal image shows astrocyte (green) adhering to the mouse brain section (j). (From Wyss-Coray et al., 2003.)
Primary Papers
- Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med. 2003 Apr;9(4):453-7. PubMed.
- Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J, Higgs R, Liu F, Malkani S, Bales KR, Paul SM. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med. 2004 Jul;10(7):719-26. PubMed.
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Aβ transport across BBB via RAGE, LRP, P-Glycoprotein
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[Copyright 2004 Cell Press.]
LRP-mediated transport of Aβ across mouse blood-brain barrier in vivo. (A) Efflux of microinjected, mutant (Dutch/Iowa) versus wild-type Aβ40 across the BBB. (B) Efflux across the BBB of Aβ40, Aβ42, and mutant Aβ in the absence and presence of unlabeled Aβ. Shows Aβ monomers in brain homogenates after microinfusion of Aβ mixture into brain interstitial fluid. (C) Ki values for LRP-mediated efflux at the BBB of Aβ40, Aβ42, and mutant Aβ plotted against Aβ β-sheet content. (D) Aβ40 and Aβ42 efflux across BBB in RAP knockout versus wild-type mice. (From Deane et al., 2003.)
[Copyright 2005 American Society for Clinical Investigation.]
Pharmacological inhibition of Pgp with intravenous injection of XF9575 increases Aβ levels in brain ISF measured by in vivo micro dialysis. (From Cirrito et al., 2005.)
Primary Papers
- Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003 Jul;9(7):907-13. PubMed.
- Deane R, Wu Z, Sagare A, Davis J, Du Yan S, Hamm K, Xu F, Parisi M, LaRue B, Hu HW, Spijkers P, Guo H, Song X, Lenting PJ, Van Nostrand WE, Zlokovic BV. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron. 2004 Aug 5;43(3):333-44. PubMed.
- Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DM. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest. 2005 Nov;115(11):3285-90. PubMed.
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White matter lesions implicate oligodendrocytes, demyelination
Primary Papers
- Bartzokis G, Cummings JL, Sultzer D, Henderson VW, Nuechterlein KH, Mintz J. White matter structural integrity in healthy aging adults and patients with Alzheimer disease: a magnetic resonance imaging study. Arch Neurol. 2003 Mar;60(3):393-8. PubMed.
- Bartzokis G. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Neurobiol Aging. 2004 Jan;25(1):5-18; author reply 49-62. PubMed.
- Mitew S, Kirkcaldie MT, Halliday GM, Shepherd CE, Vickers JC, Dickson TC. Focal demyelination in Alzheimer's disease and transgenic mouse models. Acta Neuropathol. 2010 May;119(5):567-77. PubMed.
Four proteins make up active γ-secretase complex
[Courtesy of Christian Haass.]
Primary Papers
- Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003 May;5(5):486-8. PubMed.
- Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6382-7. PubMed.
Longitudinal fMRI shows initial increase, then loss of activation in hippocampus with decline on other AD markers
[Copyright 2010 American Academy of Neurology.]
Change in neuropsychological test scores (A) and hippocampal signal (B). The fast decliners declined more steeply in objective memory performance compared to the CDR 0 stable subjects. This decrease in memory test performance corresponded to an observed decrease in hippocampal activation. (From O'Brien et al., 2010.)
Primary Papers
- Sperling RA, Bates JF, Chua EF, Cocchiarella AJ, Rentz DM, Rosen BR, Schacter DL, Albert MS. fMRI studies of associative encoding in young and elderly controls and mild Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2003 Jan;74(1):44-50. PubMed.
- O'Brien JL, O'Keefe KM, Laviolette PS, Deluca AN, Blacker D, Dickerson BC, Sperling RA. Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline. Neurology. 2010 Jun 15;74(24):1969-76. PubMed.
Head Injury increases risk
[Copyright 2003 BMJ Publishing Group Ltd.]
Odds ratio and 95 percent confidence intervals for each of the 15 studies and for all studies combined. (From Felminger et al., 2003.)
Primary Papers
- Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A. Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry. 2003 Jul;74(7):857-62. PubMed.
Primary Links
- AlzRisk: Head Injury
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Triple and quintuple transgenic mice model faster disease course
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[Copyright 2003 Cell Press.]
This image summarizes generation of the 3×Tg-AD, aka "triple transgenic" mice. They express APPSwe, tauP301L, and PS1 M146V mutations. Their elevated steady-state levels of βAPP and tau proteins (D) enable rapid development of neuropathology. (From Oddo et al., 2003).
[Copyright 2003 Cell Press.]
Aβ deposition precedes tau pathology in 3×Tg-AD mice. (A) Neocortex; Aβ immunoreactivity first appears intraneuronally. (B, C) Low- and high-magnification showing extracellular Aβ deposits in layers 4 to 5 of neocortex. (D, E) Hippocampi of six- and 12-month-old 3×Tg-AD mice shows intraneuronal Aβ staining in CA1 pyramidal neurons, then extracellular Aβ deposits. (F) High-magnification of (E). (G, H) Human tau immunoreactivity first appears in hippocampus, intensifies with age. (I) High magnification of (H). (From Oddo et al., 2003.)
[Copyright 2006 Society of Neuroscience.]
(A) 5XFAD mice express 3 FAD mutations in APP and two FAD mutations in PS1. (B) Immunoblot analysis of 5XFAD lines shows expression levels of transgene-derived APP and PS1. (From Oakley et al., 2006.)
[Copyright 2006 Society of Neuroscience.]
Cerebral Aβ42 levels increase rapidly in 5XFAD lines. (From Oakley et al., 2006.)
[Copyright 2006 Society of Neuroscience.]
Rapid cerebral amyloid deposition and gliosis in 5XFAD line Tg6799. Serial sections of hippocampus and cortex from two- (A, E, I, M), 4 (B, F, J, N), 6 (C, G, K, O), and nine-month-old (D, H, L, P) 5xTg mice were stained with antibodies against Aβ42 (A–D), Aβ40 (E–H), GFAP (I–L), and microglia (M–P). Amyloid deposition began in deep cortex and subiculum at two months and then spread into other brain regions. (From Oakley et al., 2006.)
Primary Papers
- 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. 2003 Jul 31;39(3):409-21. PubMed.
- Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006 Oct 4;26(40):10129-40. PubMed.
- Grueninger F, Bohrmann B, Czech C, Ballard TM, Frey JR, Weidensteiner C, von Kienlin M, Ozmen L. Phosphorylation of Tau at S422 is enhanced by Abeta in TauPS2APP triple transgenic mice. Neurobiol Dis. 2010 Feb;37(2):294-306. PubMed.
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Mice expressing only normal human tau
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[Copyright 2003 John Wiley & Sons, Inc.]
Abnormal accumulation of phosphorylated tau in cell bodies and dendrites of human tau mice occurs with aging. Cell body staining was absent in six-week-old hippocampus (a, d) and neocortex (g). Tau accumulation in cell bodies appeared by three months of age in hippocampus (b, e) and neocortex (h). Tau staining was strong by 13 months in hippocampus (c, f) and neocortex (i). (From Andorfer et al., 2003.)
[Copyright 2003 John Wiley & Sons, Inc.]
Immunoelectron microscopy shows accumulated, aggregated tau in the somatodendritic compartments of cortical and pyramidal hippocampal cells. (A) Tau aggregates (white arrows) in neuronal cell body in hippocampus of nine-month-old human tau mouse. The aggregation is similar to that in (b) human AD brain in early, pre-tangle stage of pathology. EM of 12-month-old htau mouse brain (c) shows abundant aggregates in dendrites. High magnification (d, e) shows aggregates to be curved. (From Andorfer et al., 2003.)
Primary Papers
- Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem. 2003 Aug;86(3):582-90. PubMed.
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