Upload
m-l
View
217
Download
5
Embed Size (px)
Citation preview
The remarkable properties of amyloid-b derivedfrom human Alzheimer’s disease brain: swingingthe streetlight
This scientific commentary refers to ‘Highly potent soluble
amyloid-b seeds in human Alzheimer brain but not cerebrospinal
fluid’ by Fritschi et al. (doi: 10.1093/brain/awu255).
Despite many years of intensive study, the specific amyloid-bspecies in the human brain responsible for the pathophysiological
processes underlying Alzheimer’s disease have yet to be identified.
In part, this may be because we have been ‘searching under the
streetlight’: examination of other sources of amyloid-b such as
synthetic preparations, material derived from the brains of trans-
genic animals, and amyloid-b recovered from human CSF after
lumbar puncture has been much more convenient than direct
evaluation of human brain-derived material. However, telltale
signs over the last several years have indicated that amyloid-bderived from human brain may have properties or constituents
that are qualitatively and quantitatively different from those of
amyloid-b from other sources. The paper by Fritschi et al.
(2014) from Mathias Jucker’s group in this issue of Brain is a
major contribution to this line of investigation. Notably, the
paper provides perhaps the most definitive evidence yet that
human brain-derived amyloid-b has fundamentally dissimilar prop-
erties to human CSF-derived material.
Specifically, Fritschi et al. demonstrate that 51 attomole (10�18
moles) of water-soluble amyloid-b from frozen human Alzheimer’s
disease brain tissue is sufficient to induce accelerated amyloid-bplaque deposition when injected into the brains of young APP
transgenic mice. In contrast, human CSF from patients with de-
mentia of the Alzheimer’s type containing over 100 000 times
greater total mass of amyloid-b failed to affect amyloid-deposition
when injected in the same manner. Neither intrinsic anti-aggrega-
tion activity in CSF, nor freeze-thaw effects could explain these
results; and CSF from transgenic mice behaved similarly, excluding
any effect of species. The same lab has previously reported that
synthetic amyloid-b at 100–1000-fold higher concentrations also
fails to induce plaque deposition (Meyer-Luehmann et al., 2006).
Furthermore, neither synthetic amyloid-b dimers nor protofibrils,
mixed synthetic amyloid-b plus astrocyte-derived apolipoprotein E
particles, nor cell-culture derived amyloid-b immunoreactive spe-
cies induce in vivo plaque deposition (Meyer-Luehmann et al.,
2006).
The explanation for these remarkable observations is not at all
clear. By way of tantalizing hints, Fritschi et al. reveal that the
amyloid-b immunoreactive particles are larger in the human
Alzheimer’s disease brain lysates than in the CSF, and their
in vitro particle seeding activity is higher. Furthermore, the
human brain material contains readily detectable N-terminally
truncated amyloid-b species such as amyloid-b4–40 and amyloid-
b4–42, whereas CSF contains primarily full length amyloid-b and
C-terminally truncated species such as amyloid-b1–17 and amyloid-
b1–38. The truncation analyses were based on matrix-assisted laser
desorption/ionization (MALDI) mass spectrometry. An important
future direction will be to include higher resolution assessments of
the material using techniques such as liquid chromatography with
tandem mass spectrometry (LC-MS/MS) to build confidence in the
identifications of amyloid-b species given the complexity of the
material. Additional mass spectrometry approaches to identify
other post-translational modifications and co-associated proteins
will also be of great interest. Furthermore, while the observations
of relative differences are likely to be solid and are based on well-
designed controls, quantitation of amyloid-b at the attomole level
is certainly challenging, particularly given its propensity for non-
linear behaviour. Future refinements will be needed in order to
perform quantitatively precise studies at this scale.
The results presented by Fritschi et al. are perhaps the most
dramatic example of an emerging theme; the vast functional di-
versity within the ‘amyloid-b-ome’. Other examples include the
following: Noguchi et al. (2009) reported that large soluble amyl-
oid-b-containing assemblies termed amylospheroids, extracted
from human Alzheimer’s disease brain lysates, caused apoptosis
of rat septal neurons in culture at concentrations �40-fold lower
than required for synthetic amyloid-b aggregates of similar size
and immunoreactivity profile. Jin et al. (2011) revealed that
small (� 8 kDa) amyloid-b immunoreactive species derived from
human Alzheimer’s disease brain caused cytoskeletal disruption
in cultured rat hippocampal neurons at concentrations 1000-fold
lower than required for synthetic amyloid-b dimers. Moreover,
Langer et al. (2011) found that a sub-fraction accounting for
50.05% of total brain amyloid-b from transgenic mouse brain
was responsible for 30% of amyloid-b aggregate seeding activity
in vivo (Langer et al., 2011).
An important avenue for future investigations will be to deter-
mine the specific relationship between these N-terminal modifica-
tions of amyloid-b and induction of amyloid-b aggregation
in vivo. The specific forms of amyloid-b detected by mass spec-
trometry may be just the tip of the iceberg; many other post-
translationally modified forms of amyloid-b have been described
recently (Bayer and Wirths, 2014). Furthermore, the ultimate bio-
logical activity is likely to be governed most directly by the 3D
structures of amyloid-b assemblies, which may require advanced
methods of assessment such as pulsed hydrogen–deuterium
exchange and fast photochemical oxidation mass spectrometry
for characterization (Gau et al., 2013; Zhang et al., 2013).
Importantly, the relationship between aggregate seeding activity
and synaptic toxicity, tau-related pathophysiological processes,
and inflammatory responses remains to be established; it is pos-
sible in principle that these events are dissociable with different
structural determinants. However, oligomeric forms of amyloid-bderived from human Alzheimer’s disease brain seem to be the
2874 | Brain 2014: 137; 2872–2878 Scientific Commentaries
by guest on Novem
ber 2, 2014D
ownloaded from
most potent triggers for neurotoxicity, and in reports analogous to
the paper by Fritschi et al., amyloid-b oligomers seems to be pre-
sent in human Alzheimer’s disease CSF at concentrations many
orders of magnitude lower than in brain tissue lysates, if at all
(Xia et al., 2009; Esparza et al., 2013; Savage et al., 2014).
In conclusion, with the efforts of Fritschi et al., as well as several
other groups in recent years, the streetlight is now beginning to
swing around to illuminate the human brain directly.
Hopefully this is where we will find the keys to developing ef-
fective therapeutics for Alzheimer’s disease.
David L. Brody and Michael L. Gross
Washington University, USA
Correspondence to: David L. Brody
E-mail: [email protected]
doi:10.1093/brain/awu261
ReferencesBayer TA, Wirths O. Focusing the amyloid cascade hypothesis on
N-truncated Abeta peptides as drug targets against Alzheimer’s dis-
ease. Acta Neuropathologica 2014; 127: 787–801.
Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM,et al. Amyloid-beta oligomerization in Alzheimer dementia versus high-
pathology controls. Ann Neurol 2013; 73: 104–119.
Fritschi S, Langer F, Kaeser S, Maia L, Portelius E, Pinotsi D, et al. Highly
soluble Ab seeds in human Alzheimer’s brain but not cerebrospinalfluid. Brain 2014; 137: 2909–15.
Gau BC, Chen J, Gross ML. Fast photochemical oxidation of proteins for
comparing solvent-accessibility changes accompanying protein folding:
data processing and application to barstar. Biochim Biophys Acta 2013;
1834: 1230–8.
Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ. Soluble
amyloid beta-protein dimers isolated from Alzheimer cortex directly
induce Tau hyperphosphorylation and neuritic degeneration. Proc
Natl Acad Sci USA 2011; 108: 5819–24.
Langer F, Eisele YS, Fritschi SK, Staufenbiel M, Walker LC, Jucker M.
Soluble Abeta seeds are potent inducers of cerebral beta-amyloid de-
position. J Neurosci 2011; 31: 14488–95.
Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S,
Schaefer C, Kilger E, et al. Exogenous induction of cerebral beta-
amyloidogenesis is governed by agent and host. Science 2006; 313:
1781–4.
Noguchi A, Matsumura S, Dezawa M, Tada M, Yanazawa M, Ito A,
et al. Isolation and characterization of patient-derived, toxic, high
mass amyloid beta-protein (Abeta) assembly from Alzheimer disease
brains. J Biol Chem 2009; 284: 32895–905.
Savage MJ, Kalinina J, Wolfe A, Tugusheva K, Korn R, Cash-Mason T,
et al. A sensitive abeta oligomer assay discriminates
Alzheimer’s and aged control cerebrospinal fluid. J Neurosci 2014;
34: 2884–97.Xia W, Yang T, Shankar G, Smith IM, Shen Y, Walsh DM, et al.
A specific enzyme-linked immunosorbent assay for
measuring beta-amyloid protein oligomers in human plasma and
brain tissue of patients with Alzheimer disease. Arch Neurol 2009;
66: 190–9.Zhang Y, Rempel DL, Zhang J, Sharma AK, Mirica LM, Gross ML. Pulsed
hydrogen-deuterium exchange mass spectrometry probes conform-
ational changes in amyloid beta (Abeta) peptide aggregation. Proc
Natl Acad Sci USA 2013; 110: 14604–9.
A serum microRNA signature for amyotrophiclateral sclersosis reveals convergent RNAprocessing defects and identifiespresymptomatic mutation carriers
This scientific commentary refers to ‘Serum microRNAs in pa-
tients with genetic amyotrophic lateral sclerosis and pre-manifest
mutation carriers’ by Freischmidt et al. (doi: 10.1093/brain/
awu249).
Defective RNA processing has occupied centre stage in the patho-
genesis of amyotrophic lateral sclerosis (ALS) since the identifica-
tion of TARDBP (also known as TDP-43) inclusions in 95% of
cases and pathogenic mutations in RNA processing genes such
as TARDBP, FUS and MATR3 (Sreedharan et al., 2008; Vance
et al., 2009; Johnson et al., 2014). FUS and TARDBP are known
to regulate mRNA transcription, splicing, stability and transport
(Tollervey et al., 2011; Rogelj et al., 2012) but they are also
part of the large Drosha complex that regulates microRNA
(miRNA) biogenesis (Gregory et al., 2004). Dysregulation of
miRNA expression has been shown in many cancers and more
recently in Alzheimer’s disease and is predicted to play a mechan-
istic role and/or be an indirect biomarker of disease.
In this issue of Brain, Freischmidt et al. (2014) report that levels
of a specific subset of miRNAs are reduced in the serum of pa-
tients with familial and sporadic ALS, and that these reductions are
even detectable in presymptomatic carriers of pathogenic ALS mu-
tations (Freischmidt et al., 2014). Some caution is required as pa-
tient numbers are small and some samples required pooling for
analysis, but if these results can be replicated in larger cohorts
then this will become a landmark study. Robust serum miRNA
biomarkers would aid early diagnosis and therefore early treat-
ment, and identify at-risk asymptomatic mutation carriers with
Scientific Commentaries Brain 2014: 137; 2872–2878 | 2875
by guest on Novem
ber 2, 2014D
ownloaded from