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

In the paper

“progressive N-truncation increases the propensity of aggregation [146, 165] and toxicity [23]”

What the sources say

• Not checked yetcites [146] Pike CJ, Overman MJ, Cotman CW (1995) Amino-terminal deletions enhance aggregation of beta-amyloid peptides in vitro. J Biol Chem 270:23895–23898 source
• Not checked yetcites [165] Schlenzig D, Manhart S, Cinar Y et al (2009) Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry 48:7072–7078 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

In the paper

“Experimental therapies, such as Aβ immunotherapy [8, 53, 138, 164, 178], were not only shown to reduce cerebral Aβ, but even more importantly, to improve behavior in transgenic mouse models of AD-like cerebral β-amyloidosis.”

What the sources say

• Not checked yetcites [8] Bard F, Cannon C, Barbour R et al (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6:916–919 source
• Not checked yetcites [53] Golde TE, Das P, Levites Y (2009) Quantitative and mechanistic studies of Abeta immunotherapy. CNS Neurol Disord Drug Targets 8:31–49 source
• Not checked yetcites [138] Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM (2004) Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43:321–332 source
• Not checked yetcites [164] Schenk D, Barbour R, Dunn W et al (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177 source
• Not checked yetcites [178] Solomon B (2007) Clinical immunologic approaches for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs 16:819–828 source

In the paper

“In 1993 the first biological paper appeared on the presence of Aβ within cells [201].”

What the sources say

• Not checked yetcites [201] Wertkin AM, Turner RS, Pleasure SJ et al (1993) Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides. Proc Natl Acad Sci USA 90:9513–9517 source

In the paper

“Current data suggest a hierarchy in the development of AD with aging, that emerging evidence increasingly supports begins with declining levels of Aβ42 in cerebrospinal fluid (CSF) and accumulation of intraneuronal Aβ42”

In the paper

“these pan-Aβ antibodies directed at the Aβ domain detect not only Aβ peptides but also the normally much more abundant full-length APP, and additionally, other Aβ-containing APP fragments such as β-secretase cleaved APP βCTFs”

In the paper

“An intracellular environment should be more favorable for allowing Aβ aggregation, since intracellular organelles can have a lower pH, higher metal ion concentrations and provide a limited space.”

In the paper

“This publication described prominent early Aβ42 labeling of AD vulnerable neuron cell bodies, but not their nuclei, in pre-plaque Down syndrome brains and also non-Down syndrome brains, particularly those with early AD neuropathological changes.”

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

In the paper

“Thus, while aberrant Aβ42 accumulation begins in endosomes, mitochondrial Aβ may be a critical contributor in the pathological cascade leading to neuronal dysfunction and pathology in AD [33, 103, 149].”

What the sources say

• Not checked yetcites [33] Chen X, Yan SD (2006) Mitochondrial Abeta: a potential cause of metabolic dysfunction in Alzheimer’s disease. IUBMB Life 58:686–694 source
• Not checked yetcites [103] Lin MT, Beal MF (2006) Alzheimer’s APP mangles mitochondria. Nat Med 12:1241–1243 source
• Not checked yetcites [149] Reddy PH (2008) Mitochondrial medicine for aging and neurodegenerative diseases. Neuromolecular Med 10:291–315 source

In the paper

“Detection of intraneuronal Aβ is even more challenging in human brain, where in contrast to AD transgenic mice, APP is not over-expressed and FAD mutations that elevate Aβ42 are rare.”

In the paper

“Moreover, intraneuronal Aβ is best appreciated at early stages of pathology in AD transgenic mouse and human AD brains, while postmortem human AD brains are more often examined at end stages of disease.”

In the paper

“a recent study indicated that cognitive decline in AD tracked best with the membranous pool of Aβ42 in brain tissue from human AD [180]; it was concluded that this membrane-associated Aβ42 was cell associated and reflected intraneuronal Aβ42.”

What the sources say

• Not checked yetcites [180] Steinerman JR, Irizarry M, Scarmeas N et al (2008) Distinct pools of beta-amyloid in Alzheimer disease-affected brain: a clinicopathologic study. Arch Neurol 65:906–912 source

In the paper

“C-terminal specific Aβ42 antibodies typically are best at detecting Aβ42 monomers, and have minimal reactivity against oligomers larger than trimers [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

“Although the presence of intraneuronal Aβ accumulation has now been widely detected in brains of human Down syndrome and AD, and transgenic models of AD, skepticism persists.”

In the paper

“Studies have increasingly differentiated between soluble and insoluble pools of Aβ within the brain, where it is the increase in the soluble pool of Aβ42 that tracks best with cognitive decline in AD [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

“Postmortem interval, pre-treatments, counter-stains, fixation and post-fixation, detergent, and blocking solutions, all can influence interpretation of immuno-histochemistry, and also that of intraneuronal Aβ [34, 39].”

What the sources say

• Not checked yetcites [34] Christensen DZ, Bayer TA, Wirths O (2009) Formic acid is essential for immunohistochemical detection of aggregated intraneuronal Abeta peptides in mouse models of Alzheimer’s disease. Brain Res 1301:116–125 source
• Not checked yetcites [39] D’Andrea MR, Reiser PA, Polkovitch DA et al (2003) The use of formic acid to embellish amyloid plaque detection in Alzheimer’s disease tissues misguides key observations. Neurosci Lett 342:114–118 source

In the paper

“it is not common knowledge that commercial antibodies can change. Particularly polyclonal antibodies can have batch to batch variations that can significantly affect interpretation.”

In the paper

“When the same amounts of Aβ1-42 were incubated over time, levels of Aβ42 assayed by a standard non-denaturing ELISA appeared to decline as a function of time, while denaturing Western blotting indicated that levels were actually unchanged; this occurred because ongoing Aβ aggregation progressively blocked access of the Aβ42 antibody in the ELISA.”

What the sources say

• Not checked yetcites [181] Stenh C, Englund H, Lord A et al (2005) Amyloid-beta oligomers are inefficiently measured by enzyme-linked immunosorbent assay. Ann Neurol 58:147–150 source

In the paper

“It should be noted that there also is variability in the degree of intraneuronal Aβ labeling [60], which is more pronounced in human compared to AD transgenic mouse brains.”

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

In the paper

“One possible explanation for this concern is that Aβ aggregation leads to conformational changes and thereby the reduced ability of Aβ antibodies in detecting their antigens.”

In the paper

“Since the triple transgenic mouse expressing mutant APP, PS1 and tau develops early Aβ accumulation in CA1 hippocampal neurons and later tau paired helical filaments [140], the stratum lacunosum-moleculare (SLM) of hippocampus containing the CA1 distal apical dendrites was selectively examined by immuno-EM.”

What the sources say

• 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

“An example of this is the early accumulation of Aβ42 within layer II neuron cell bodies of the entorhinal cortex and early plaques at their axonal terminal fields in the outer molecular layer of the dentate in the hippocampus [60].”

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

In the paper

“a recent E693Delta mutation in APP was reported to be associated with an AD clinical phenotype in the absence of plaques; cells harboring this mutation were shown to have reduced Aβ secretion and increased intracellular Aβ accumulation and oligomerization [134].”

What the sources say

• 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

In the paper

“In one study, Aβ-induced abnormalities in MVB endocytic sorting were demonstrated in APP mutant neurons, which appeared to be due to impairment of the ubiquitin proteasome system (UPS; [2]).”

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

“The lack of correlation between Aβ plaques and cognitive decline in AD may relate to person-to-person differences in the ability of inflammatory cells to effectively remove Aβ plaques from the brain.”

In the paper

“Specifically, immuno-histochemical data support that neuron cell bodies with early intraneuronal Aβ42 accumulation are those that go on to develop NFTs [60, 140], while their terminal fields are sites of early plaque pathology.”

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 [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

“Remarkably, the SLM showed not only prominent early Aβ42 increases but also the earliest labeling with antibodies against phospho-tau, such as the well-established antibody AT8.”

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 most marked accumulation of intraneuronal Aβ42 occurs in distal neurites and synaptic compartments as determined by immuno-EM [188] that cannot be visualized effectively by light or standard immuno-fluorescence microscopy.”

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

“Indirect support for synapse-specific Aβ generation also comes from PS1 conditional knockout mice, which showed aberrant accumulation of APP βCTFs in distal axons/pre-synaptic compartments [162] and also some anatomically selective accumulation in distal dendrites/post-synaptic compartments (personal observations).”

What the sources say

• Not checked yetcites [162] Saura CA, Chen G, Malkani S et al (2005) Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci 25:6755–6764 source

In the paper

“These data build on previous studies to provide an early temporal and spatial relationship of the main constituents of the two neuropathological hallmarks of AD and thereby also link them with synapse pathology in AD.”

In the paper

“Synapses have long been viewed as critical sites of AD pathology [6, 28, 112, 119, 168] and diverse evidence had supported that synapses are major sites of Aβ pathology and also generation.”

What the sources say

• Not checked yetcites [6] Arendt T (2009) Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol 118:167–179 source
• Not checked yetcites [28] Coleman PD, Yao PJ (2003) Synaptic slaughter in Alzheimer’s disease. Neurobiol Aging 24:1023–1027 source
• Not checked yetcites [112] Masliah E, Crews L, Hansen L (2006) Synaptic remodeling during aging and in Alzheimer’s disease. J Alzheimers Dis 9:91–99 source
• Not checked yetcites [119] Mesulam MM (1999) Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles. Neuron 24:521–529 source
• Not checked yetcites [168] Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791 source

In the paper

“Overall, emerging work on intraneuronal Aβ is most consistent with the scenario of aging, and other genetic and environmental risk factors, such as apoEε4 and head injury, respectively, leading to up-regulation and then oligomerization of intraneuronal Aβ42 in distal neurites and synapses, which then leads directly to destruction of neurites and synapses from within (Fig. 3).”

In the paper

“In particular dense core plaques appear to be derived from neuron cell bodies, although even here it is possible that dendritic Aβ42 accumulations are the inciting event.”

In the paper

“Many in vitro and in vivo studies have shown that exogenous application of Aβ alters synaptic plasticity [170, 198] and important synaptic proteins [3, 79, 177], although how precisely this occurs remains unclear.”

What the sources say

• Not checked yetcites [170] Shankar GM, Li S, Mehta TH et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842 source
• Not checked yetcites [198] Walsh DM, Klyubin I, Fadeeva JV et al (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539 source
• 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
• Not checked yetcites [177] Snyder EM, Nong Y, Almeida CG et al (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8:1051–1058 source

In the paper

“At first this seems difficult to reconcile with recent data showing that patients in coma have marked reductions in extracellular Aβ42, which rises and falls with cognitive improvement and decline, respectively [16].”

What the sources say

• Not checked yetcites [16] Brody DL, Magnoni S, Schwetye KE et al (2008) Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science 321:1221–1224 source

In the paper

“Degree of intraneuronal Aβ42 might tightly correlate with synaptic dysfunction, whereas synapse-independent factors might dissociate plaque burden from cognitive decline, for example, genetic heterogeneity may exist in the ability of inflammatory cells to remove plaques.”

In the paper

“That this pathological accumulation is most prominent in distal neurites and synapses of AD transgenic mice provided the first direct association between Aβ and synapse pathologies in the brain [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

“Remarkably, it was demonstrated that Aβ antibodies can reduce the intraneuronal pool of Aβ in vivo [138] and in vitro [189], which for the latter was shown to required Aβ antibody internalization.”

What the sources say

• Not checked yetcites [138] Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM (2004) Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43:321–332 source
• Not checked yetcites [189] Tampellini D, Magrane J, Takahashi RH et al (2007) Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta and protect against synaptic alterations. J Biol Chem 282:18895–18906 source

In the paper

“Another explanation for the potential Aβ/synaptic activity paradox is that sites of high cerebral activity, in the default system, are indeed sites of early AD neuropathology [18, 179], but not necessarily because of increased Aβ secretion.”

What the sources say

• Not checked yetcites [18] Buckner RL, Snyder AZ, Shannon BJ et al (2005) Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 25:7709–7717 source
• 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

“Furthermore, Aβ secretion is also increased with cognitive activity, since patients in coma showed elevations in Aβ with cognitive improvement; a subsequent decline in cognitive function correlated with decline in interstitial/extracellular Aβ levels [16].”

What the sources say

• Not checked yetcites [16] Brody DL, Magnoni S, Schwetye KE et al (2008) Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science 321:1221–1224 source

In the paper

“Furthermore, functional brain imaging shows reduced resting brain activity in subjects with AD, and even in genetically at-risk subjects decades prior to predicted cognitive symptoms [150].”

What the sources say

• Not checked yetcites [150] Reiman EM, Chen K, Alexander GE et al (2004) Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci USA 101:284–289 source

In the paper

“Work in the 1990s had shown that extracellular Aβ1-42 led to marked up-regulation of endogenously generated Aβ42 [51, 211], which also occurs in neurons [190].”

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
• Not checked yetcites [211] Yang AJ, Chandswangbhuvana D, Shu T, Henschen A, Glabe CG (1999) Intracellular accumulation of insoluble, newly synthesized abeta n-42 in amyloid precursor protein-transfected cells that have been treated with Abeta1-42. J Biol Chem 274:20650–20656 source
• 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

“Recently, additional evidence pointed to the importance of amyloidogenic processing of APP, and therefore potentially intraneuronal Aβ, in extracellular Aβ-induced synapse dysfunction [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 protease shown to most efficiently degrade Aβ, neprilysin [81], was reported to be critical in synaptic activity-induced intraneuronal Aβ42 reduction [190].”

What the sources say

• Not checked yetcites [81] Iwata N, Tsubuki S, Takaki Y et al (2000) Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 6:143–150 source
• 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

“Similar to tau aggregation developing within neurons but then as ghost tangles no longer within living neurons, Aβ accumulation also begins intracellularly and ends up extracellular following neuritic degeneration.”

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.”

What the sources say

• Not checked yetcites [20] Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM (2005) Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders. Neurobiol Aging 26:645–654 source
• Not checked yetcites [50] Fukami S, Watanabe K, Iwata N et al (2002) Abeta-degrading endopeptidase, neprilysin, in mouse brain: synaptic and axonal localization inversely correlating with Abeta pathology. Neurosci Res 43:39–56 source