Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease

In the paper

“FAD mutations actually cause a relatively greater increase in intracellular compared to secreted Aβ ([202], and unpublished observations).”

What the sources say

• Not checked yetcites [202] Wild-Bode C, Yamazaki T, Capell A et al (1997) Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42. J Biol Chem 272:16085–16088 source

In the paper

“other biochemical Aβ detection methods, such as immunoprecipitation, can vastly underestimate total Aβ levels, since spiking of samples with a defined amount of Aβ1-42 reveals that only a very small fraction of the added Aβ can subsequently be detected (personal observations).”

In the paper

“In addition, dementia pugilistica that develops in professional boxers [31], while characterized by significant tauopathy and comparably less amyloid pathology, limited mainly to diffuse plaques [27], also shows considerable intraneuronal Aβ42 (Fig. 4c).”

What the sources say

• Not checked yetcites [31] Corsellis JA, Bruton CJ, Freeman-Browne D (1973) The aftermath of boxing. Psychol Med 3:270–303 source
• Not checked yetcites [27] Clinton J, Ambler MW, Roberts GW (1991) Post-traumatic Alzheimer’s disease: preponderance of a single plaque type. Neuropathol Appl Neurobiol 17:69–74 source

In the paper

“We have observed marked up-regulation of intraneuronal Aβ42 in surrounding neurites and neuron cell bodies near needle track injuries in the rodent brains 48 to 72 hours following brain injury (Fig. 4a).”

In the paper

“By immuno-EM these increases in Aβ42 occurred predominantly in endosomes (Fig. 4b).”

In the paper

“The aberrant accumulation of aggregated β-amyloid peptides (Aβ) as plaques is a hallmark of Alzheimer’s disease (AD) neuropathology”

• Also stated in: § Introduction · plain

  “The anatomically selective and differential accumulation of Aβ plaques and neurofibrillary tangles (NFTs) are neuropathological hallmarks of AD [193, 207].”

What the sources say

• Not checked yetcites [193] Thal DR, Del Tredici K, Braak H (2004) Neurodegeneration in normal brain aging and disease. Sci Aging Knowl Environ 9:pe26 source
• Not checked yetcites [207] WorkingGroup (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 18:S1–S2

In the paper

“research studies have reported that loss of synaptic markers, specifically of the pre-synaptic protein synaptophysin, is the best brain correlate of cognitive decline in AD [40, 42, 168, 184, 192].”

What the sources say

• Not checked yetcites [40] Davies CA, Mann DM, Sumpter PQ, Yates PO (1987) A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease. J Neurol Sci 78:151–164 source
• Not checked yetcites [42] DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464 source
• Not checked yetcites [168] Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791 source
• Not checked yetcites [184] Sze CI, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ (1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 56:933–944 source
• Not checked yetcites [192] Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580 source

In the paper

“Current evidence argues against another APP cleavage product being more important than specifically the Aβ42 isoform in AD.”

In the paper

“the earliest Aβ42 in plaques appears to be N-truncated [98].”

What the sources say

• Not checked yetcites [98] Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ (1996) Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 3:16–32 source

In the paper

“the slightly longer Aβ42 species that is specifically linked with FAD is also the first Aβ species deposited in cerebral plaques [82].”

What the sources say

• Not checked yetcites [82] Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13:45–53 source

In the paper

“the added copy of APP in trisomy 21 was known to be associated with the early and invariable development of AD pathology in Down syndrome [52].”

What the sources say

• Not checked yetcites [52] Goate AM, Haynes AR, Owen MJ et al (1989) Predisposing locus for Alzheimer’s disease on chromosome 21. Lancet 1:352–355 source

In the paper

“all autosomal dominant mutations associated with rare familial forms of early onset AD in the amyloid precursor protein (APP) and presenilin (PS) 1 and 2 were shown to increase the proportion of Aβ42 to Aβ40 peptides.”

• Also stated in: § Familial AD mutations · plain

  “the common denominator among FAD mutations is not an increase in Aβ secretion, but an increase in the Aβ42 to Aβ40 ratio [71].”

What the sources say

• Not checked yetcites [71] Hecimovic S, Wang J, Dolios G, Martinez M, Wang R, Goate AM (2004) Mutations in APP have independent effects on Abeta and CTFgamma generation. Neurobiol Dis 17:205–218 source

In the paper

“apoEε4 has been consistently associated with increased cerebral Aβ load [88].”

What the sources say

• Not checked yetcites [88] Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63:287–303 source

In the paper

“AD transgenic mice showed physiological [32, 74, 77, 124] and neuritic alterations [22, 125] prior to plaques”

What the sources say

• Not checked yetcites [32] Chapman PF, White GL, Jones MW et al (1999) Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 2:271–276 source
• Not checked yetcites [74] Holcomb L, Gordon MN, McGowan E et al (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4:97–100 source
• Not checked yetcites [77] Hsia AY, Masliah E, McConlogue L et al (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci USA 96:3228–3233 source
• Not checked yetcites [124] Moechars D, Dewachter I, Lorent K et al (1999) Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 274:6483–6492 source
• Not checked yetcites [22] Capetillo-Zarate E, Staufenbiel M, Abramowski D et al (2006) Selective vulnerability of different types of commissural neurons for amyloid {beta}-protein-induced neurodegeneration in APP23 mice correlates with dendritic tree morphology. Brain 129:2992–3005 source
• Not checked yetcites [125] Moolman DL, Vitolo OV, Vonsattel JP, Shelanski ML (2004) Dendrite and dendritic spine alterations in Alzheimer models. J Neurocytol 33:377–387 source

In the paper

“This reactivity of Aβ/APP antibodies to APP has contributed to considerable misunderstanding with regards to the presence of intraneuronal Aβ in the field.”

In the paper

“The subsequent development of antibodies directed at the free C-terminal ends of Aβ40 or Aβ42 [82] led to the ability to differentiate Aβ from APP labeling”

What the sources say

• Not checked yetcites [82] Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13:45–53 source

In the paper

“Two publications appeared in January 2000 on the intraneuronal accumulation of particularly Aβ42 by light microscopy within neurons of human brain.”

What the sources say

• Not checked yetcites [123] Mochizuki A, Tamaoka A, Shimohata A, Komatsuzaki Y, Shoji S (2000) Abeta42-positive non-pyramidal neurons around amyloid plaques in Alzheimer’s disease. Lancet 355:42–43 source
• Not checked yetcites [60] Gouras GK, Tsai J, Naslund J et al (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156:15–20 source

In the paper

“Endosomal Aβ42 labeling by immuno-EM has since been confirmed by other groups [49, 95, 143].”

What the sources say

• Not checked yetcites [49] Friedrich RP, Tepper K, Ronicke R et al (2010) Mechanism of amyloid plaque formation suggests an intracellular basis of A{beta} pathogenicity. Proc Natl Acad Sci USA 107:1942–1947 source
• Not checked yetcites [95] Langui D, Girardot N, El Hachimi KH et al (2004) Subcellular topography of neuronal Abeta peptide in APPxPS1 transgenic mice. Am J Pathol 165:1465–1477 source
• Not checked yetcites [143] Pastorino L, Sun A, Lu PJ et al (2006) The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 440:528–534 source

In the paper

“this and subsequent studies noted an apparent decline in intraneuronal Aβ42 labeling with advancing plaque pathology [95, 139].”

What the sources say

• Not checked yetcites [95] Langui D, Girardot N, El Hachimi KH et al (2004) Subcellular topography of neuronal Abeta peptide in APPxPS1 transgenic mice. Am J Pathol 165:1465–1477 source
• Not checked yetcites [139] Oddo S, Caccamo A, Smith IF, Green KN, LaFerla FM (2006) A dynamic relationship between intracellular and extracellular pools of Abeta. Am J Pathol 168:184–194 source

In the paper

“neurons in normal wild-type mouse, rat and human brains showed localization of Aβ42 primarily associated with endosomal organelles, often identifiable on electron micrographs as late endosomal multivesicular bodies (MVBs; [188]).”

What the sources say

• Not checked yetcites [188] Takahashi RH, Milner TA, Li F et al (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161:1869–1879 source

In the paper

“Subsequent work showed that particularly the disease-linked Aβ42 peptide, rather than the more abundantly secreted Aβ40 peptide, increased with differentiation and time in culture within clonal NT2 cells that can develop a neuron-like phenotype [174, 195].”

What the sources say

• Not checked yetcites [174] Skovronsky DM, Doms RW, Lee VM (1998) Detection of a novel intraneuronal pool of insoluble amyloid beta protein that accumulates with time in culture. J Cell Biol 141:1031–1039 source
• Not checked yetcites [195] Turner RS, Suzuki N, Chyung AS, Younkin SG, Lee VM (1996) Amyloids beta40 and beta42 are generated intracellularly in cultured human neurons and their secretion increases with maturation. J Biol Chem 271:8966–8970 source

In the paper

“the triple transgenic mouse harboring mutations in APP, PS1 and tau was shown to develop prominent intraneuronal Aβ accumulation that coincided with the emergence of behavioral, physiological and synaptic abnormalities several months prior to Aβ plaques [12, 140].”

What the sources say

• Not checked yetcites [12] Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45:675–688 source
• Not checked yetcites [140] Oddo S, Caccamo A, Shepherd JD et al (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421 source

In the paper

“PS1/APP mutant transgenic mice were shown to have prominent intraneuronal Aβ accumulation associated with neuron cell death [23, 35, 167].”

What the sources say

• Not checked yetcites [23] Casas C, Sergeant N, Itier JM et al (2004) Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 165:1289–1300 source
• Not checked yetcites [35] Christensen DZ, Kraus SL, Flohr A, Cotel MC, Wirths O, Bayer TA (2008) Transient intraneuronal A beta rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice. Acta Neuropathol 116:647–655 source
• Not checked yetcites [167] Schmitz C, Rutten BP, Pielen A et al (2004) Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 164:1495–1502 source

In the paper

“Intriguing in vitro and in vivo studies showed that intraneuronal Aβ1-42 was particularly neurotoxic [213]”

What the sources say

• Not checked yetcites [213] Zhang Y, McLaughlin R, Goodyer C, LeBlanc A (2002) Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons. J Cell Biol 156:519–529 source

In the paper

“Aβ42 labeling was shown to be absent in neurons of APP knockout mouse brains”

What the sources say

• Not checked yetcites [188] Takahashi RH, Milner TA, Li F et al (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161:1869–1879 source

In the paper

“lack of plaque formation in intraneuronal Aβ42 accumulating transgenic mice with concomitant neurodegeneration [36, 93] limited conclusions that could be drawn to the human disease, since pathological diagnosis of AD requires Aβ plaques.”

What the sources say

• Not checked yetcites [36] Chui DH, Tanahashi H, Ozawa K et al (1999) Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat Med 5:560–564 source
• Not checked yetcites [93] LaFerla FM, Tinkle BT, Bieberich CJ, Haudenschild CC, Jay G (1995) The Alzheimer’s A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat Genet 9:21–30 source

In the paper

“dual-immuno-EM further indicated that APP has a different subcellular localization (primarily Golgi apparatus) compared to Aβ42 (primarily endosomes).”

What the sources say

• Not checked yetcites [188] Takahashi RH, Milner TA, Li F et al (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161:1869–1879 source

In the paper

“biochemical studies on human AD brain indicated that the soluble pool of Aβ42 correlated best with degree of cognitive loss [108, 118, 130].”

What the sources say

• Not checked yetcites [108] Lue LF, Kuo YM, Roher AE et al (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 155:853–862 source
• Not checked yetcites [118] McLean CA, Cherny RA, Fraser FW et al (1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46:860–866 source
• Not checked yetcites [130] Naslund J, Haroutunian V, Mohs R et al (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283:1571–1577 source

In the paper

“Confirmation for the presence of intraneuronal Aβ was provided by a study that showed the disappearance of intraneuronal Aβ in AD transgenic mice when Aβ levels were reduced either by treatment with γ-secretase inhibitor or by crossing the mice with BACE knockout mice [145].”

What the sources say

• Not checked yetcites [145] Philipson O, Lannfelt L, Nilsson LN (2009) Genetic and pharmacological evidence of intraneuronal Abeta accumulation in APP transgenic mice. FEBS Lett 583:3021–3026 source

In the paper

“Overall, the data for the early accumulation of Aβ in mitochondria appear weaker compared to that for endosomes.”

In the paper

“FAD mutations can even decrease secretion of the most abundantly released Aβ isoform, Aβ40, while still increasing the Aβ42 to Aβ40 ratio [90, 134, 173].”

What the sources say

• Not checked yetcites [90] Kumar-Singh S, De Jonghe C, Cruts M et al (2000) Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer’s disease. Hum Mol Genet 9:2589–2598 source
• Not checked yetcites [134] Nishitsuji K, Tomiyama T, Ishibashi K et al (2009) The E693Delta mutation in amyloid precursor protein increases intracellular accumulation of amyloid beta oligomers and causes endoplasmic reticulum stress-induced apoptosis in cultured cells. Am J Pathol 174:957–969 source
• Not checked yetcites [173] Siman R, Reaume AG, Savage MJ et al (2000) Presenilin-1 P264L knock-in mutation: differential effects on abeta production, amyloid deposition, and neuronal vulnerability. J Neurosci 20:8717–8726 source

In the paper

“The aggregation-prone nature of Aβ makes the accurate biochemical analysis of intraneuronal Aβ particularly challenging.”

In the paper

“Therefore, neurons should, and eventually do, stain with Aβ/APP antibodies that also detect APP, if one uses appropriate immuno-histochemical procedures, including allowing for longer reaction times.”

In the paper

“coincident illness and agonal state likely contribute to variability of intraneuronal Aβ labeling in human brain.”

In the paper

“The relative dearth of recent biochemical evidence on intraneuronal Aβ has contributed in delaying the acceptance of intraneuronal Aβ.”

In the paper

“Not seeing intraneuronal Aβ in brain can be due to many factors other than its absence.”

In the paper

“N-terminal Aβ1-x/βCTF-specific antibodies also fail to label N-truncated Aβ42 peptides that appear to be particularly important in AD [60, 98, 157, 158, 206].”

What the sources say

• Not checked yetcites [60] Gouras GK, Tsai J, Naslund J et al (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156:15–20 source
• Not checked yetcites [98] Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ (1996) Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 3:16–32 source
• Not checked yetcites [157] Saido TC, Yamao-Harigaya W, Iwatsubo T, Kawashima S (1996) Amino- and carboxyl-terminal heterogeneity of beta-amyloid peptides deposited in human brain. Neurosci Lett 215:173–176 source
• Not checked yetcites [158] Saido TC, Iwatsubo T, Mann DM, Shimada H, Ihara Y, Kawashima S (1995) Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron 14:457–466 source
• Not checked yetcites [206] Wirths O, Bethge T, Marcello A et al (2010) Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer’s disease cases. J Neural Transm 117:85–96 source

In the paper

“These immuno-EM studies were the first to directly associate Aβ with synaptic and neuritic damage in the brain.”

In the paper

“Thus, the above caveats further underscore that the absence of labeling does not have to reflect absence of Aβ within neurons.”

In the paper

“a subsequent immuno-EM study demonstrated that intraneuronal accumulation of higher molecular weight Aβ42 oligomers (antibody M16; [210]) was invariably associated with neuritic degeneration, even prior to plaques, in vulnerable distal neurites and synaptic compartments in brains of AD transgenic mice and human AD [187].”

What the sources say

• Not checked yetcites [187] Takahashi RH, Almeida CG, Kearney PF et al (2004) Oligomerization of Alzheimer’s beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci 24:3592–3599 source

In the paper

“As Aβ aggregates from monomers to oligomers and then fibrils, the conformation and antibody accessibility of peptide epitopes within Aβ can change.”

What the sources say

• Not checked yetcites [87] Kayed R, Head E, Sarsoza F et al (2007) Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener 2:18 source

In the paper

“Emerging data from AD transgenic mice support that Aβ40 might even be protective against cerebral amyloid [117].”

What the sources say

• Not checked yetcites [117] McGowan E, Pickford F, Kim J et al (2005) Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47:191–199 source

In the paper

“the use of Aβ/APP antibodies has been an issue in the acceptance of intraneuronal Aβ.”

In the paper

“Biochemical determination of Aβ levels in brain can also show considerable variation between studies.”

In the paper

“The implications for intraneuronal Aβ in AD include providing new insights into a link between Aβ and tau pathologies that were formerly considered to be separate and how these two pathologies relate to synapse pathology [186].”

What the sources say

• Not checked yetcites [186] Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK (2008) Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses. Neurobiol Aging. doi: 101016/jneurobiolaging200807021

In the paper

“It had been known that even in APP mutant transgenic mice hyperphosphorylated tau can be seen within some dystrophic neurites around plaques [14].”

What the sources say

• Not checked yetcites [14] Blanchard V, Moussaoui S, Czech C et al (2003) Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice. Exp Neurol 184:247–263 source

In the paper

“Reactive inflammatory cells and plaques may have both protective and detrimental roles that contribute to AD pathogenesis.”

In the paper

“By beginning within neurons, Aβ is more directly accessible to altering tau, the principle component of the other neuropathological hallmark of AD.”

In the paper

“The Arctic FAD mutation within the mid-region of Aβ [133] primarily increase the propensity for Aβ aggregation rather than secretion.”

What the sources say

• Not checked yetcites [133] Nilsberth C, Westlind-Danielsson A, Eckman CB et al (2001) The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat Neurosci 4:887–893 source

In the paper

“Since accumulation of Aβ42 within AD vulnerable neurons has been associated with physiological, pathological and behavioral abnormalities even prior to plaques [12, 140, 187, 188], the evidence is mounting that intraneuronal Aβ42 is the driving force in Aβ-related AD pathogenesis [9, 58, 92].”

What the sources say

• Not checked yetcites [9] Bayer A, Wirths O (2010) Intracellular accumulation of amyloid-beta—a predictor for synaptic dysfunction and neuron loss in Alzheimer’s disease. Front Ag Neurosci 2:8. doi: 103389/fnagi201000008
• Not checked yetcites [58] Gouras GK, Almeida CG, Takahashi RH (2005) Intraneuronal Abeta accumulation and origin of plaques in Alzheimer’s disease. Neurobiol Aging 26:1235–1244 source
• Not checked yetcites [92] LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 8:499–509 source

In the paper

“Remarkably, dystrophic neurites around plaques showed co-localization of phospho-tau with Aβ42 in AD transgenic mice and human AD [186].”

What the sources say

• Not checked yetcites [186] Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK (2008) Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses. Neurobiol Aging. doi: 101016/jneurobiolaging200807021

In the paper

“FAD transgenic mouse models with the highest level of amyloidogenic Aβ display particularly prominent early intraneuronal Aβ accumulation [89, 106, 196].”

What the sources say

• Not checked yetcites [89] Knobloch M, Konietzko U, Krebs DC, Nitsch RM (2007) Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol Aging 28:1297–1306 source
• Not checked yetcites [106] Lord A, Kalimo H, Eckman C, Zhang XQ, Lannfelt L, Nilsson LN (2006) The Arctic Alzheimer mutation facilitates early intraneuronal Abeta aggregation and senile plaque formation in transgenic mice. Neurobiol Aging 27:67–77 source
• Not checked yetcites [196] Van Broeck B, Vanhoutte G, Pirici D et al (2008) Intraneuronal amyloid beta and reduced brain volume in a novel APP T714I mouse model for Alzheimer’s disease. Neurobiol Aging 29:241–252 source

In the paper

“Emerging data, such as FAD mutations noted above, and the direct association of intraneuronal Aβ42 with subcellular pathology [187, 188], cell death [23, 167], and behavioral and physiological abnormalities, even prior to plaques, in AD transgenic mouse models [140], are providing increasing evidence for the importance of intraneuronal Aβ.”

What the sources say

• Not checked yetcites [187] Takahashi RH, Almeida CG, Kearney PF et al (2004) Oligomerization of Alzheimer’s beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci 24:3592–3599 source
• Not checked yetcites [188] Takahashi RH, Milner TA, Li F et al (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161:1869–1879 source
• Not checked yetcites [23] Casas C, Sergeant N, Itier JM et al (2004) Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 165:1289–1300 source
• Not checked yetcites [167] Schmitz C, Rutten BP, Pielen A et al (2004) Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 164:1495–1502 source
• Not checked yetcites [140] Oddo S, Caccamo A, Shepherd JD et al (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421 source

In the paper

“a subset of patients from the aborted Wyeth/ELAN active Aβ vaccine trial that were studied at autopsy showed Aβ plaque removal in the absence of cognitive improvement [75].”

What the sources say

• Not checked yetcites [75] Holmes C, Boche D, Wilkinson D et al (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223 source

In the paper

“By dual-immuno-EM phospho-tau was specifically evident in markedly Aβ42 accumulating, distal CA1 apical dendrites and their post-synaptic compartments in the SLM [186].”

What the sources say

• Not checked yetcites [186] Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK (2008) Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses. Neurobiol Aging. doi: 101016/jneurobiolaging200807021

In the paper

“The subsequent formation of more amorphous plaques reflect remnants of this destruction further shaped by activated inflammatory cells.”

In the paper

“Cumulative pathological data on intraneuronal Aβ accumulation support a scenario of increased Aβ42 in vulnerable distal neurites and synapses leading to their destruction from within (Fig. 3).”

In the paper

“The combination of increasing soluble Aβ42 in brain, declining CSF Aβ42, and immuno-EM evidence of concomitant intraneuronal Aβ42 accumulation, seem to strongly suggest that the soluble pool of Aβ42 in the brain that correlates with disease progression mainly reflects intraneuronal Aβ42.”

In the paper

“Remarkably, this MPM study of AD transgenic mouse brain in vivo also described the emergence of dystrophic neurites in areas distant from plaques that appeared and, at times, even disappeared, although intraneuronal Aβ was not examined in these neurites.”

What the sources say

• Not checked yetcites [120] Meyer-Luehmann M, Spires-Jones TL, Prada C et al (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature 451:720–724 source

In the paper

“Thus, the nidus of Aβ plaques develops from within neurites at a time course that could also fit that of plaque formation determined by multiphoton microscopy (MPM) occurring within a day [120].”

What the sources say

• Not checked yetcites [120] Meyer-Luehmann M, Spires-Jones TL, Prada C et al (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature 451:720–724 source

In the paper

“In fact synaptic activity was recently shown to promote APP transport down neurites to synapses [190].”

What the sources say

• Not checked yetcites [190] Tampellini D, Rahman N, Gallo EF et al (2009) Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci 29:9704–9713 source

In the paper

“Thus, tau, normally localized to axons, showed early mislocalization specifically in aberrant Aβ42 accumulating distal dendrites.”

In the paper

“In contrast, lesioning of another projection pathway, that from the locus coeruleus, was reported to increase plaque pathology in terminal fields of the cerebral cortex [72].”

What the sources say

• Not checked yetcites [72] Heneka MT, Ramanathan M, Jacobs AH et al (2006) Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci 26:1343–1354 source

In the paper

“At the same time, a subset of plaques appear to emerge directly from intracellular Aβ accumulating neuron cell bodies [38, 60].”

What the sources say

• Not checked yetcites [38] D’Andrea MR, Nagele RG, Wang HY, Peterson PA, Lee DH (2001) Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer’s disease. Histopathology 38:120–134 source
• Not checked yetcites [60] Gouras GK, Tsai J, Naslund J et al (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156:15–20 source

In the paper

“Furthermore, extracellular Aβ1-42 oligomers preferentially target synapses when added to neurons [43, 91].”

What the sources say

• Not checked yetcites [43] Deshpande A, Kawai H, Metherate R, Glabe CG, Busciglio J (2009) A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses. J Neurosci 29:4004–4015 source
• Not checked yetcites [91] Lacor PN, Buniel MC, Chang L et al (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 24:10191–10200 source

In the paper

“Plaque development in terminal processes can help explain the lack of neuron cell death in most AD transgenic mice in the presence of considerable plaque pathology, since neuron cell bodies can survive following loss of some neurites and synapses.”

In the paper

“Immuno-EM for PS1 localized this critical component of the γ-secretase complex particularly to endosomes in distal neurites, including in both pre- and post-synaptic compartments [94].”

What the sources say

• Not checked yetcites [94] Lah JJ, Heilman CJ, Nash NR et al (1997) Light and electron microscopic localization of presenilin-1 in primate brain. J Neurosci 17:1971–1980 source

In the paper

“APP is transported down both axons and dendrites and Aβ appears to be generated preferentially at synapses [25, 54, 85].”

What the sources say

• Not checked yetcites [25] Cirrito JR, Kang JE, Lee J et al (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58:42–51 source
• Not checked yetcites [54] Goldsbury C, Mocanu MM, Thies E et al (2006) Inhibition of APP trafficking by tau protein does not increase the generation of amyloid-beta peptides. Traffic 7:873–888 source
• Not checked yetcites [85] Kamenetz F, Tomita T, Hsieh H et al (2003) APP processing and synaptic function. Neuron 37:925–937 source

In the paper

“Lesioning of the perforant pathway originating in the early AD prone entorhinal cortex leads to reduced plaque pathology at terminal synaptic fields in the hippocampus [96, 171].”

What the sources say

• Not checked yetcites [96] Lazarov O, Lee M, Peterson DA, Sisodia SS (2002) Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci 22:9785–9793 source
• Not checked yetcites [171] Sheng JG, Price DL, Koliatsos VE (2002) Disruption of corticocortical connections ameliorates amyloid burden in terminal fields in a transgenic model of Abeta amyloidosis. J Neurosci 22:9794–9799 source

In the paper

“Immuno-EM images of completely abnormal Aβ42 accumulating dystrophic neurites [187, 188], lacking the normal microtubule tracks required for organelle trafficking, secretion and exocytosis, argue against the active secretion of aggregating Aβ42 from neuritis prior to the dissolution of the plasma membrane [95].”

What the sources say

• Not checked yetcites [187] Takahashi RH, Almeida CG, Kearney PF et al (2004) Oligomerization of Alzheimer’s beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci 24:3592–3599 source
• Not checked yetcites [188] Takahashi RH, Milner TA, Li F et al (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161:1869–1879 source
• Not checked yetcites [95] Langui D, Girardot N, El Hachimi KH et al (2004) Subcellular topography of neuronal Abeta peptide in APPxPS1 transgenic mice. Am J Pathol 165:1465–1477 source

In the paper

“APP is transported down both axons and dendrites and Aβ appears to be generated preferentially at synapses [25, 54, 85].”

What the sources say

• Not checked yetcites [25] Cirrito JR, Kang JE, Lee J et al (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58:42–51 source
• Not checked yetcites [54] Goldsbury C, Mocanu MM, Thies E et al (2006) Inhibition of APP trafficking by tau protein does not increase the generation of amyloid-beta peptides. Traffic 7:873–888 source
• Not checked yetcites [85] Kamenetz F, Tomita T, Hsieh H et al (2003) APP processing and synaptic function. Neuron 37:925–937 source

In the paper

“Remarkably, it was shown that extracellular Aβ1-42 was not toxic to APP knockout neurons [107] and that even point mutations in the NPXY motif in the C-terminus of APP block toxicity [169].”

What the sources say

• Not checked yetcites [169] Shaked GM, Kummer MP, Lu DC, Galvan V, Bredesen DE, Koo EH (2006) Abeta induces cell death by direct interaction with its cognate extracellular domain on APP (APP 597–624). Faseb J 20:1254–1256 source

In the paper

“Using the well established endocytosis of the epidermal growth factor receptor (EGFR), this study demonstrated that specifically the MVB sorting pathway, and not internalization or the recycling pathway, was altered in Aβ accumulating neurons.”

What the sources say

• Not checked yetcites [2] Almeida CG, Takahashi RH, Gouras GK (2006) Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci 26:4277–4288 source

In the paper

“An intriguing study showed that shifting the ratio of Aβ42 to Aβ40 in APP mutant transgenic mice under a neuron-specific promoter shifted the preponderance of parenychmal Aβ42 plaques to vascular Aβ40 amyloid [73].”

What the sources say

• Not checked yetcites [73] Herzig MC, Winkler DT, Burgermeister P et al (2004) Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 7:954–960 source

In the paper

“Remarkably, it was shown that extracellular Aβ1-42 was not toxic to APP knockout neurons [107] and that even point mutations in the NPXY motif in the C-terminus of APP block toxicity [169].”

What the sources say

• Not checked yetcites [107] Lorenzo A, Yuan M, Zhang Z et al (2000) Amyloid beta interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer’s disease. Nat Neurosci 3:460–464 source

In the paper

“The study went on to provide evidence that abnormalities in MVB sorting were due to Aβ-dependent alterations in the ubiquitin-proteasome system (UPS).”

What the sources say

• Not checked yetcites [2] Almeida CG, Takahashi RH, Gouras GK (2006) Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci 26:4277–4288 source

In the paper

“Overall, more prominent increases in Aβ42 accumulation were observed in distal dendrites compared to axons [188], although there are anatomical differences, and it remains possible that either axons or dendrites are the initial site of intraneuronal Aβ pathology.”

What the sources say

• Not checked yetcites [188] Takahashi RH, Milner TA, Li F et al (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161:1869–1879 source

In the paper

“It is of interest that among the earliest and most significantly Aβ-altered synaptic proteins are AMPA glutamate receptor subunits [3, 79], that are particularly important for synaptic plasticity.”

What the sources say

• Not checked yetcites [3] Almeida CG, Tampellini D, Takahashi RH et al (2005) Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis 20:187–198 source
• Not checked yetcites [79] Hsieh H, Boehm J, Sato C et al (2006) AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52:831–843 source

In the paper

“Immuno-histochemical and –EM observations support that both distal and proximal dendritic arborizations are important sites of Aβ42 accumulation and plaque formation (Fig. 3).”

In the paper

“While Aβ immuno-EM provides evidence for all forms of plaques, including diffuse plaques, representing destruction of neurites, there are several possible reasons for why degree of plaque pathology is not as good a measure of cognitive dysfunction compared to soluble, and we hypothesize intraneuronal, Aβ42.”

In the paper

“Thus, head trauma provides an example of extracellular–appearing amyloid developing in the setting of what has been shown to be a state of reduced interstitial, extracellular Aβ and, as experimental evidence now indicates, concomitant intraneuronal Aβ42 accumulation.”

In the paper

“Individuals, including children, who died following coma not long after severe head trauma were shown to develop amorphous cerebral Aβ plaques [152].”

What the sources say

• Not checked yetcites [152] Roberts GW, Gentleman SM, Lynch A, Murray L, Landon M, Graham DI (1994) Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 57:419–425 source

In the paper

“This supports that amyloid angiopathy derives from perivascular drainage of Aβ40 generated by neurons [61, 200].”

What the sources say

• Not checked yetcites [61] Grinberg LT, Thal DR (2010) Vascular pathology in the aged human brain. Acta Neuropathol 119:277–290 source
• Not checked yetcites [200] Weller RO, Djuanda E, Yow HY, Carare RO (2009) Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol 117:1–14 source

In the paper

“Remarkably, APP mutant neurons showed differential alterations in synaptic proteins [3] that resembled those that have been described in AD brain, such as early loss of the pre-synaptic protein synaptophysin [113, 163, 192] and the post-synaptic protein PSD-95 [63].”

What the sources say

• Not checked yetcites [3] Almeida CG, Tampellini D, Takahashi RH et al (2005) Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis 20:187–198 source
• Not checked yetcites [113] Masliah E, Mallory M, Hansen L, DeTeresa R, Alford M, Terry R (1994) Synaptic and neuritic alterations during the progression of Alzheimer’s disease. Neurosci Lett 174:67–72 source
• Not checked yetcites [163] Scheff SW, Price DA (2003) Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies. Neurobiol Aging 24:1029–1046 source
• Not checked yetcites [192] Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580 source
• Not checked yetcites [63] Gylys KH, Fein JA, Yang F, Wiley DJ, Miller CA, Cole GM (2004) Synaptic changes in Alzheimer’s disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence. Am J Pathol 165:1809–1817 source

In the paper

“Furthermore, a recent imaging study supports that the presence of plaques by Pittsburgh compound B (PiB) PET amyloid imaging even in those diagnosed as cognitively normal does reflect deficits on functional imaging [179].”

What the sources say

• Not checked yetcites [179] Sperling RA, Laviolette PS, O’Keefe K et al (2009) Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron 63:178–188 source

In the paper

“A recent neurobiological study showed that it was reduction of intraneuronal rather than extracellular Aβ that correlated with synaptic improvement [190].”

What the sources say

• Not checked yetcites [190] Tampellini D, Rahman N, Gallo EF et al (2009) Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci 29:9704–9713 source

In the paper

“Thus, microscopic Aβ plaque pathology should also be able to go unnoticed, at least for a while.”

In the paper

“Rather these sites of high metabolic activity also generate high levels of reactive oxygen species that might contribute to a progressively decreased ability to effectively degrade intraneuronal Aβ42 with aging.”

In the paper

“Hyperexcitability is present in AD brain [142] and epilepsy was shown to promote plaque pathology [110].”

What the sources say

• Not checked yetcites [110] Mackenzie IR, Miller LA (1994) Senile plaques in temporal lobe epilepsy. Acta Neuropathol 87:504–510 source

In the paper

“Recently it is becoming apparent that the earliest diagnostic change indicating that an individual without known cognitive deficits will go on to decline cognitively and develop AD is a drop in levels of Aβ42 in the CSF [15, 48].”

What the sources say

• Not checked yetcites [15] Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6:131–144 source
• Not checked yetcites [48] Fagan AM, Head D, Shah AR et al (2009) Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol 65:176–183 source

In the paper

“Moreover, synaptic activity was recently shown to reduce the intraneuronal pool of Aβ in vitro and in vivo [190].”

What the sources say

• Not checked yetcites [190] Tampellini D, Rahman N, Gallo EF et al (2009) Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci 29:9704–9713 source

In the paper

“The neuropathological and biological evidence on intraneuronal Aβ accumulation increasingly suggest that this is the critical pool of Aβ that needs to be contained.”

In the paper

“Hyperexcitability is present in AD brain [142] and epilepsy was shown to promote plaque pathology [110].”

What the sources say

• Not checked yetcites [142] Palop JJ, Mucke L (2009) Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol 66:435–440 source

In the paper

“Thus, reduced cerebral activity with AD should imply reduced Aβ secretion in AD brain.”

In the paper

“That the best predictor for conversion to MCI and then AD is a decrease in the levels of extracellular Aβ42 might have seemed surprising to proponents of the prevalent extracellular Aβ cascade hypothesis.”

What the sources say

• Not checked yetcites [15] Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6:131–144 source
• Not checked yetcites [48] Fagan AM, Head D, Shah AR et al (2009) Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol 65:176–183 source

In the paper

“Intraneuronal Aβ42 accumulation therefore clearly can be detrimental already prior to plaques and obvious cognitive decline.”

In the paper

“A more parsimonious and novel explanation, that also is in line with the Aβ42 immuno-EM neuropathological data in brain and new insights relating to head injury described above, is that extracellular Aβ42 declines because secretion of Aβ42 is reduced as it accumulates instead within neurons.”

In the paper

“At the same time, postmortem neuropathological studies and PET amyloid imaging indicate that individuals without known cognitive dysfunction can nevertheless have considerable plaque pathology.”

In the paper

“The triple transgenic mouse supports the notion that elevated intraneuronal Aβ can cause cognitive decline prior to plaques and tangles [12].”

What the sources say

• Not checked yetcites [12] Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45:675–688 source

In the paper

“It needs to be stressed again that by immuno-EM high molecular weight Aβ42 oligomers are consistently associated with pathology within neurites even prior to plaques [187].”

What the sources say

• Not checked yetcites [187] Takahashi RH, Almeida CG, Kearney PF et al (2004) Oligomerization of Alzheimer’s beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci 24:3592–3599 source

In the paper

“Synaptic activity has been shown to increase the secretion of Aβ in hippocampal slices and living rodent brain [26, 85].”

What the sources say

• Not checked yetcites [26] Cirrito JR, Yamada KA, Finn MB et al (2005) Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48:913–922 source
• Not checked yetcites [85] Kamenetz F, Tomita T, Hsieh H et al (2003) APP processing and synaptic function. Neuron 37:925–937 source

In the paper

“Although it is thought that only a small amount of extracellular can be internalized into neurons [156, 211], Aβ42 appears to a have a prion-like ability of transferring an altered aggregation state from the outside to the inside of cells [51].”

What the sources say

• Not checked yetcites [51] Glabe C (2001) Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease. J Mol Neurosci 17:137–145 source

In the paper

“In addition, alterations of extracellular Aβ on selective synaptic proteins mirrored those from intraneuronal Aβ accumulation [3].”

What the sources say

• Not checked yetcites [3] Almeida CG, Tampellini D, Takahashi RH et al (2005) Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis 20:187–198 source

In the paper

“Given that neprilysin localizes to synapses and declines with aging [20, 50], declining neprilysin may be important in the age-related intraneuronal accumulation of Aβ in synapses.”

In the paper

“Emerging evidence on intraneuronal Aβ strongly argues that this needs to change.”