SAGE-Hindawi Access to Research
International Journal of Alzheimer’s Disease
Volume 2011, Article ID 894938, 6 pages
MicroRNAsand Alzheimer’sDiseaseMouse Models:
Charlotte Delay1,2andS´ ebastienS.H´ ebert1,2
1Axe Neurosciences, Centre de Recherche du CHUQ (CHUL), Qu´ ebec, QC, Canada G1V4G2
2D´ epartement de Psychiatrie et de Neurosciences, Facult´ e de M´ edecine, Universit´ e Laval, Qu´ ebec, QC, Canada G1V0A6
Correspondence should be addressed to S´ ebastien S. H´ ebert, email@example.com
Received 25 May 2011; Accepted 13 June 2011
Academic Editor: Marcella Reale
Copyright © 2011 C. Delay and S. S. H´ ebert. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Evidence from clinical trials as well as from studies performed in animal models suggest that both amyloid and tau pathologies
function in concert with other factors to cause the severe neurodegeneration and dementia in Alzheimer’s disease (AD) patients.
Accumulating data in the literature suggest that microRNAs (miRNAs) could be such factors. These conserved, small nonprotein-
coding RNAs are essential for neuronal function and survival and have been implicated in the regulation of key genes involved in
genetic and sporadic AD. The study of miRNA changes in AD mouse models provides an appealing approach to address the cause-
consequence relationship between miRNA dysfunction and AD pathology in humans. Mouse models also provide attractive tools
to validate miRNA targets in vivo and provide unique platforms to study the role of specific miRNA-dependent gene pathways in
disease. Finally, mouse models may be exploited for miRNA diagnostics in the fight against AD.
Alzheimer’s disease (AD) is the most common form of
dementia worldwide. It is characterized by the accumu-
lation of extracellular amyloid (senile) plaques, composed
mainly of Aβ peptides, and intracellular neurofibrillary
tangles, containing abnormally aggregated and hyperphos-
phorylated Tau protein. The Aβ peptides are generated
by the sequential cleavage of Amyloid precursor protein
(APP) by β-secretase (BACE1-dependent) and γ-secretase
familial forms of AD caused mutations in the APP and PSEN
genes, Hardy and Selkoe proposed the “amyloid cascade
hypothesis”, which suggests that Aβ overproduction alone
is sufficient to trigger the molecular events leading to both
two decades, several breakthroughs have been made with
regard to modeling AD pathology in vivo in mice, providing
important tools for various areas of basic and translational
research. Several AD mouse models harboring human APP,
PSEN, and/or MAPT (Tau) transgenes support to some
extent the amyloid cascade hypothesis; however, recent
clinical trials in humans suggest that amyloid-dependent
signaling pathways are insufficient to cause the severe
neurodegeneration and dementia in AD patients [3–5]. It
is therefore perhaps not surprising that most, if not all, AD
mouse models, albeit displaying massive Aβ deposits and/or
tangles, do not recapitulate the full-blown neuropathological
biochemical, cellular, and morphological changes observed
in AD brain [6–8]. This opens the door to the identification
of novel factors important for AD development, which
could equally serve as potential diagnostic and therapeutic
The past years have witnessed an explosion of papers
linking microRNA (miRNA) dysfunction to human disease,
many others. Perhaps expectedly, mounting evidence also
involve miRNAs in neurodegenerative disorders, with poten-
tial implications in AD [9, 10], Parkinson’s disease (PD)
, Huntington’s disease (HD) [12, 13], frontotemporal
dementia (FTD) [14, 15], and amyotrophic lateral sclerosis
(ALS) . Because of the rapid growth of miRNA research
in general, it is likely other neurodegenerative disorders will
soon be added to this list.
2International Journal of Alzheimer’s Disease
Recent RNA deep sequencing efforts have identified
more than 1400 miRNA genes in the human genome (700
in mice) (miRBase.org). Several of these are specifically
expressed in the brain, where they are proposed to function
in neuronal processes such as neurite outgrowth and synapse
formation [17, 18]. The biogenesis and mode of action
of miRNA molecules in mammals is complex and has
extensively been reviewed elsewhere (see, e.g., [19–22]).
In short, miRNA precursors (pre-miRs) are cleaved in
the cytoplasm by the RNase Dicer to produce small (∼
21nt in length) single-stranded nonprotein-coding RNAs.
These latter function as part of the RNA-induced silencing
complex (RISC), which targets specific mRNA transcripts
with imperfect complementarity. Binding of the miRNA
to its target leads to translation inhibition and/or mRNA
degradation [23, 24], which ultimately leads to down-
regulation of the encoded protein. It is predicted that 25
to 70% of all protein-coding genes can be regulated by
miRNAs, depending on the developmental, cellular, and/or
physiological context. Moreover, each miRNA can target
up to several hundred transcripts in vivo, thus potentially
regulating multiple biological pathways, including those
implicated in neuronal survival . It is therefore not
surprising that genetic ablation of Dicer in the brain, which
leads to an overall reduction in miRNA production, results
in rapid neurodegeneration [26–28].
The somewhat humble introduction of miRNAs in the
AD field came in 2007 when Lukiw studied the expression
levels of 13 brain miRNAs in control and AD patients,
some of which were specifically altered in disease .
Since then, several groups have performed global miRNA
system [32, 33]. These profiling experiments tend to show a
disease-specific” miRNAs, including miR-29, miR-9, miR-
15a, miR-181c, miR-101, miR-106b, miR-146a, and miR-
107, which have been identified in two or more indepen-
dent studies. Interestingly, several of these miRNAs may
have a direct role in modulating APP (miR-106, miR-
101) [34–36] or BACE1 (miR-29, miR-107) [9, 37–39]
expression, therefore potentially contributing to increase
amyloid production. Because (1) miRNAs regulate APP
and BACE1 expression, whose increased protein levels are
linked to genetic and sporadic AD, respectively (reviewed
in [21, 40]) and (2) miRNAs control several pathways
involved in neuronal function, inflammation and survival,
miRNA research provides an interesting new perspective
to study the underlying mechanisms involved in AD
2.miRNA-Deficiency andthe ADBrain
While depleting all miRNAs remain a conceptually crude
Dicer-deficient brain and AD brain. For instance, neuronal
Dicer conditional knockout (cKO) mice develop progres-
sive neurodegeneration, have reduced brain size, enlarged
ventricles, neuroinflammation, apoptosis (in some cases),
as well as impaired dendritic branching, and spine length
[26, 41, 42]. In addition, neuronal Dicer cKO mice exhibit
AD-like hyperphosphorylation of endogenous tau ,
which is not observed in nontransgenic mice. These latter
results succeed previous studies in the fly linking tau toxicity
to miRNA dysfunction . Interestingly, specific loss of
Dicer in oligodendrocytes results in axonal degeneration
accompanied by abnormal axonal transport and endogenous
APP accumulation . This model also displays signs of
oxidative stress, and, taken together, these results point
out the importance of Dicer and miRNAs in maintain-
ing neuronal function. Although controversial, one study
suggests that neuronal Dicer deficiency promotes learning
and memory, at least at stages prior to neuronal loss .
How these observations translate to human disease remains
speculative, but nevertheless provides “proof-of-principle”
that loss (and perhaps gain) of brain miRNA function can
participate in several neuropathological features of AD.
3.miRNA Profiles fromAD Mice
Apart from the more obvious role of miRNAs in regulating
the expression of disease-related genes (e.g., APP and
BACE1), it is likely that a combination of more subtle
(direct or indirect) mechanisms alter disease progression
over years, possibly decades. As example, sustained miR-
29 deficiency may not only increase BACE1 and Aβ levels,
but also affect DNA methylation and neuronal survival [46,
47]. In addition, it remains difficult to predict whether the
observed changes in miRNA levels in humans are a cause or
consequence of the neurodegenerative process. The study of
miRNA expression profiles in AD mouse models may help to
address these questions.
Wang et al. were the first to study global miRNA
profiles from AD mice using microarrays . For this,
they used the APPSwe-PS1M146L mouse model. Of the
37 differently expressed miRNAs, several (miR-20a, miR-
29a, miR-125b, miR-128a, and miR-106b) miRNAs were
significantly downregulated, while others (miR-34a, let-7,
miR-28, and miR-98) were upregulated. Interestingly, some
miRNAs were similarly shown to be affected in AD brain in
It is noteworthy that miRNA alterations were measured at 3
months of age prior to Aβ plaque formation. In most cases,
miRNA alterations were maintained or even accentuated
during amyloid plaque formation at 6 months of age,
therefore supporting the “cause” hypothesis. The increase
in miR-34a in the mutant mice is proposed to function in
regulating apoptosis via Bcl-2 modulation . In a follow-
up study, the group showed by sensitive miRNA quantitative
RT-PCR that miR-106b is upregulated in 3-month-old AD
mice but downregulated at 6 months . These changes
correlated to some extent with transforming growth factor,
beta receptor II (TβRII) expression, and a putative miR-
106b target gene . While these studies highlight the
importance of microarray validation, they also suggest a
possible transient effect of AD pathology (in this case Aβ
plaque formation) on miRNA expression and vice versa.
More recently, Schonrock et al. studied the effects
of exogenous Aβ on miRNA expression levels in mouse
International Journal of Alzheimer’s Disease3
downregulated by Aβ treatment were previously found to be
decreased in human AD brain, including miR-9, miR-181c,
miR-30c, miR-148b, miR-20b, and let-7i. Of interest, certain
miRNAs decreased concomitantly with Aβ pathology pro-
gression in vivo in APP23 mice expressing human APP751
support the “consequence” hypothesis of miRNA dysregu-
lation in AD, it is noteworthy that some miRNA molecules
became affected prior to Aβ plaque formation (like miR-409-
3p and let-7i) similar to what is seen in the Wang et al. study
(, see above). Furthermore, the expression of certain
miRNAs changed over time (from up- to downregulated or
vice versa), again supporting the transient effect on miRNA
expression during AD development.
While studying the role of actin and the actin-binding
protein cofilin in AD, Yao et al. observed decreased miR-
103 and miR-107 levels in 4-month old (Aβ plaque bearing)
Tg19959 mice that express mutant APP with KM670/671NL
and V717F FAD mutations . As mentioned above, both
miR-103 and miR-107 were shown to be decreased in MCI
and late-onset AD . The authors further showed that
these miRNA paralogues could effectively regulate cofilin
expression in vitro, providing a mechanism for the observed
increase in rod-like structures in this mouse model.
Loss of presenilin function is proposed to underlie mem-
ory impairment and neurodegeneration in the pathogenesis
of AD . Interestingly, small-scale miRNA profiling from
Psen1 KO mice with, as a result, reduced γ-secretase activity
and Aβ production, showed that miR-9 down-regulation
coincided with neurodegeneration . It is noteworthy
that miR-9 was shown to be an important regulator of
neurogenesis, both in zebrafish and mice [55, 56]. Based on
these observations, it is tempting to speculate that miR-9,
which is downregulated in AD brain, participates actively in
Candidate miRNA approaches have equally been per-
formed. For instance, Li et al. studied miR-146a expression
in five different AD mouse models, including Tg-2576, Tg-
CRND8, PSAPP, 3xTg-AD, and 5XFAD . This group
had shown earlier that miR-146a expression levels were
increased in AD brain . It turned out that miR-146a
was significantly increased in age (4- to 12-month-old) when
compared to young (1- to 2-month-old) mice, and this,
independently of the model tested . Notably, miR-146a
has repeatedly been shown to be implicated in the regulation
of the inflammatory response . Moreover, neuroinflam-
mation is thought to play a critical role in the pathogenesis
of chronic neurodegenerative diseases including AD ,
evoking the hypothesis that miR-146a overexpression in
these AD models could reflect a defense mechanism against
the deleterious effects of neuroinflammation. Interestingly,
synthetic Aβ was shown to induce miR-146a expression
in cultured human neuronal (and glial) cells . Taken
together, the abovementioned observations suggest that
miRNA-regulated gene pathways, such as the miR-146a
pathway, could function both upstream and downstream of
AD pathology (cause and consequence).
4.miRNA-Mediated Regulation of
AD GenesIn Vivo
One of the main challenges in the miRNA field is the
identification of bona fide target genes. Several genome-wide
methods are currently available to address this question,
including microarray expression analyses following miRNA
transfection/inhibition, Argonaute cross-linked immuno-
approaches [61–63]. So far, however, most miRNA studies
involving AD-related genes have relied on artificial 3?UTR
reporter systems (e.g., luciferase-based assays) as well as
single miRNA gain- or loss-of-function experiments in
cells. While these methods remain indispensable in the
validation of miRNA:mRNA targets, they rarely put both
molecules in their physiological context. In addition, it is
important to consider that some miRNA:mRNA targets
are not conserved in lower organisms such as C. elegans
and Drosophila, making extrapolations to mammalian brain
sometimes difficult (e.g., see ).
As of now, most studies addressing the role of miRNAs
in AD gene regulation have focused on APP. These have
lead to the identification of at least six miRNAs that could
regulate APP in vitro and in cells, including the miR-20a
family (i.e. miR-20a, miR-17-5p, and miR-106a/b), miR-101,
and miR-16 [40, 64–68]. Interestingly, Liu et al. showed that
miR-16 inhibition in 8-month-old SAMP8 mice, a model for
accelerated senescence, reduced endogenous APP levels by
determined. While providing the first “proof-of-principle”
of APP regulation by miRNAs in vivo, this study does not
exclude the role of other miRNAs in this process in the
brain. For instance, our preliminary data indicate that APP
mRNA levels are increased in miR-20a/17-5p double KO
mice (Hebert, S.S., unpublished observations). In addition,
is, miR-15a, miR-15b, miR-195, and miR-495 are involved
in APP regulation in vivo. Interestingly, miR-16 family
members have also been implicated in endogenous tau
phosphorylation in neurons .
While investigating the molecular mechanisms involved
in endogenous BACE1 overexpression in 6-month-old (Aβ
plaque bearing) 5XFAD , O’Connor et al. observed no
significant changes in miR-29a, miR-29b, and miR-9 levels,
previously shown to regulate BACE1 in vitro , when
compared to nontransgenic controls. Another study suggests
however, that miR-29c (the third miR-29 family member)
overexpression is sufficient to decrease endogenous BACE1
protein levels in wild-type mice . The functional effects
on BACE1 activity and Aβ production were unfortunately
not evaluated in this latter model. Boissonneault et al.
showed that BACE1 protein increases in 19-month-old
mice , an effect not observed in wild-type mice. Inter-
estingly, two miRNAs shown to regulate murine BACE1
expression in vitro, that is, miR-298 and miR-328 were
are affected in the 5XFAD and APPSwe-PS1A246E mice
remains to be determined. Lastly, Faghihi et al. showed that
4International Journal of Alzheimer’s Disease
BACE1 protein and BACE1 antisense (noncoding) transcript
levels were increased in 6-week-old Tg19959 mice .
Whether decreased miR-103/107 levels observed in this
mouse model (see Yao et al. study above) could contribute
to increase BACE1 remains to be determined. Thus, among
at least five miRNAs shown to target BACE1 in vitro, that is,
miR-29, miR-9, miR-107, miR-298, and miR-328, no clear
evidencecanbedrawnfromthese mousemodels withregard
to the physiological or pathological regulation of BACE1 by
miRNAs in vivo.
While the abovementioned results are interesting, the
overall contribution of miRNAs in BACE1 and APP expres-
sion regulation remains unclear. The use of gene knockout
mice will be indispensible to make definitive conclusions
with regard to the role of miRNAs or miRNA gene families
in BACE1, APP, and other AD-related gene expression regu-
mimics or inhibitors, will be necessary to address the cause-
miRNA functional tools will be necessary to fully investigate
the role of miRNAs in AD mouse models.
5.miRNAs asPotentialDiagnosticTools inAD
Much advancements have been made in the cancer field,
for instance, with regard to miRNAs as potential diagnostic
tools, some of which are currently available in the clinic. The
interest in miRNAs in this field comes from the fact that they
are readably detected in human body fluids, making them
attractive biological markers. In addition, miRNAs are in
general quite stable when compared to protein and/or other
a few groups have explored the role of miRNAs in blood and
CSF [32, 33], most AD-based studies have focused mainly
on soluble Aβ (and its derivatives) and tau [72, 73]. In the
fluids including exosomes . It is noteworthy that groups
Duchenne muscular dystrophy and liver injury [75, 76].
As summarized above, most studies addressing the role
of miRNAs in AD pathology remain correlative in nature,
and little or no definitive proof with regard to miRNA
target gene regulation in vivo is currently unavailable.
Addressing these issues is crucial in order to advance our
knowledge of the contribution of miRNAs, if any, in AD
neuropathology. Because mice are genetically homogenous
in nature when compared to humans, they provide unique
tools to study miRNA-regulated gene pathways in AD
development. Human profiling studies clearly indicate that
miRNA expression profiles are altered in AD brain. Whether
these changes are specific to AD or reflect an overall loss
(or gain) of miRNA function in neurodegenerative disease
remains to be determined using adequate comparative
analyses. The current profiling data from AD mice suggest
that miRNA changes equally occur in disease models, yet
some discrepancies still exist. Given our current state of
knowledge, the role of miRNAs in AD development, and
their applicability as diagnostic and perhaps therapeutic
tools into clinic, will require extensive follow-up studies
in both in vitro and animal models. Specific miRNA gene
knockout and/or transgenic mouse is required to address
these and other fascinating questions.
BACE1: Beta-site APP cleaving enzyme
FAD: Familial Alzheimer’s disease
CSF: Cerebrospinal fluid
3?UTR: 3?untranslated region.
The authors declare no conflict of interests.
This work was supported by the Scottish Rite Charitable
Foundation of Canada and the Alzheimer Society of Canada
(including a fellowship for C. Delay).
 J. Hardy and D. J. Selkoe, “The amyloid hypothesis of
Alzheimer’s disease: progress and problems on the road to
therapeutics,” Science, vol. 297, no. 5580, pp. 353–356, 2002.
 J. A. Hardy and G. A. Higgins, “Alzheimer’s disease: the
amyloid cascade hypothesis,” Science, vol. 256, no. 5054, pp.
 T. E. Golde, L. S. Schneider, and E. H. Koo, “Anti-Aβ
therapeutics in alzheimer’s disease: the need for a paradigm
shift,” Neuron, vol. 69, no. 2, pp. 203–213, 2011.
 K. Sambamurti, N. H. Greig, T. Utsuki et al., “Targets for AD
treatment: conflicting messages from γ-secretase inhibitors,”
Journal of Neurochemistry, vol. 117, no. 3, pp. 359–374, 2011.
 L.-Y. Fan and M.-J. Chiu, “Pharmacological treatment for
Alzheimer’s disease: current approaches and future strategies,”
Acta Neurologica Taiwanica, vol. 19, no. 4, pp. 228–245, 2010.
 C. Balducci and G. Forloni, “APP transgenic mice: their use
and limitations,” NeuroMolecular Medicine, vol. 13, no. 2, pp.
 K. J. Bryan, H. Lee, G. Perry, M. A. Smith, and G. Casadesus,
“Transgenic mouse models of Alzheimer’s disease: behavioral
testing and considerations,” in Methods of Behavior Analysis in
Neuroscience, CRC Press, Boca Raton, Fla, USA, 2009.
disease in mice,” Neuron, vol. 66, no. 5, pp. 631–645, 2010.
 S. S. H´ ebert, K. Horr´ e, L. Nicola¨ ı et al., “Loss of microRNA
cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates
with increased BACE1/β-secretase expression,” Proceedings
of the National Academy of Sciences of the United States of
America, vol. 105, no. 17, pp. 6415–6420, 2008.
 W. X. Wang, B. W. Rajeev, A. J. Stromberg et al., “The expres-
sion of microRNA miR-107 decreases early in Alzheimer’s
International Journal of Alzheimer’s Disease5
disease and may accelerate disease progression through reg-
ulation of β-site amyloid precursor protein-cleaving enzyme
1,” Journal of Neuroscience, vol. 28, no. 5, pp. 1213–1223, 2008.
 J. Kim, K. Inoue, J. Ishii et al., “A microRNA feedback circuit
in midbrain dopamine neurons,” Science, vol. 317, no. 5842,
pp. 1220–1224, 2007.
 A. N. Packer, Y. Xing, S. Q. Harper, L. Jones, and B. L. David-
son, “The bifunctional microRNA miR-9/miR-9∗regulates
REST and CoREST and is downregulated in Huntington’s
disease,” Journal of Neuroscience, vol. 28, no. 53, pp. 14341–
 E. Mart´ ı, L. Pantano, M. Ba˜ nez-Coronel et al., “A myriad of
miRNA variants in control and Huntington’s disease brain
regions detected by massively parallel sequencing,” Nucleic
Acids Research, vol. 38, no. 20, pp. 7219–7235, 2010.
 R. Rademakers, J. L. Eriksen, M. Baker et al., “Common
variation in the miR-659 binding-site of GRN is a major risk
factor for TDP43-positive frontotemporal dementia,” Human
Molecular Genetics, vol. 17, no. 23, pp. 3631–3642, 2008.
 W. X. Wang, B. R. Wilfred, S. K. Madathil et al., “miR-107 reg-
ulates granulin/progranulin with implications for traumatic
of Pathology, vol. 177, no. 1, pp. 334–345, 2010.
 A. H. Williams, G. Valdez, V. Moresi et al., “MicroRNA-
206 delays ALS progression and promotes regeneration of
neuromuscular synapses in mice,” Science, vol. 326, no. 5959,
pp. 1549–1554, 2009.
 R. Saba and G. M. Schratt, “MicroRNAs in neuronal devel-
opment, function and dysfunction,” Brain Research, vol. 1338,
no. C, pp. 3–13, 2010.
 R. Fiore, G. Siegel, and G. Schratt, “MicroRNA function in
neuronal development, plasticity and disease,” Biochimica et
Biophysica Acta, vol. 1779, no. 8, pp. 471–478, 2008.
 J. Krol, I. Loedige, and W. Filipowicz, “The widespread
regulation of microRNA biogenesis, function and decay,”
Nature Reviews Genetics, vol. 11, no. 9, pp. 597–610, 2010.
 K. Breving and A. Esquela-Kerscher, “The complexities of
microRNA regulation: mirandering around the rules,” Inter-
national Journal of Biochemistry and Cell Biology, vol. 42, no.
8, pp. 1316–1329, 2010.
 S. S. H´ ebert and B. De Strooper, “Alterations of the microRNA
network cause neurodegenerative disease,” Trends in Neuro-
sciences, vol. 32, no. 4, pp. 199–206, 2009.
 M. P. Perron and P. Provost, “Protein interactions and
complexes in human microRNA biogenesis and function,”
Frontiers in Bioscience, vol. 13, no. 7, pp. 2537–2547, 2008.
 V. Ambros, “The functions of animal microRNAs,” Nature,
vol. 431, no. 7006, pp. 350–355, 2004.
 S. Djuranovic, A. Nahvi, and R. Green, “A parsimonious
model for gene regulation by miRNAs,” Science, vol. 331, no.
6017, pp. 550–553, 2011.
 O. Hobert, “Gene regulation by transcription factors and
MicroRNAs,” Science, vol. 319, no. 5871, pp. 1785–1786, 2008.
 S.S.H´ ebert,A.S.Papadopoulou,P.Smithetal.,“Geneticabla-
tion of dicer in adult forebrain neurons results in abnormal
tau hyperphosphorylation and neurodegeneration,” Human
Molecular Genetics, vol. 19, no. 20, pp. 3959–3969, 2010.
 A. Schaefer, D. O’Carroll, L. T. Chan et al., “Cerebellar
neurodegeneration in the absence of microRNAs,” Journal of
Experimental Medicine, vol. 204, no. 7, pp. 1553–1558, 2007.
 T. L. Cuellar, T. H. Davis, P. T. Nelson et al., “Dicer loss
in striatal neurons produces behavioral and neuroanatomical
phenotypes in the absence of neurodegeneration,” Proceedings
of the National Academy of Sciences of the United States of
America, vol. 105, no. 14, pp. 5614–5619, 2008.
 W. J. Lukiw, “Micro-RNA speciation in fetal, adult and
Alzheimer’s disease hippocampus,” NeuroReport, vol. 18, no.
3, pp. 297–300, 2007.
 J. Nunez-Iglesias, C. C. Liu, T. E. Morgan, C. E. Finch, and
X. J. Zhou, “Joint genome-wide profiling of miRNA and
mRNA expression in Alzheimer’s disease cortex reveals altered
miRNA regulation,” PloS One, vol. 5, no. 2, Article ID e8898,
 M. Shioya, S. Obayashi, H. Tabunoki et al., “Aberrant
microRNA expression in the brains of neurodegenerative
diseases: MiR-29a decreased in Alzheimer disease brains
targets neurone navigator 3,” Neuropathology and Applied
Neurobiology, vol. 36, no. 4, pp. 320–330, 2010.
 J. P. Cogswell, J. Ward, I. A. Taylor et al., “Identification
of miRNA changes in Alzheimer’s disease brain and CSF
Journal of Alzheimer’s Disease, vol. 14, no. 1, pp. 27–41, 2008.
 H. M. Schipper, O. C. Maes, H. M. Chertkow, and E. Wang,
“MicroRNA expression in Alzheimer blood mononuclear
cells,” Gene Regulation and Systems Biology, vol. 1, pp. 1263–
Marks, “Human microRNA targets,” PLoS Biology, vol. 2, no.
11, article e363, 2004.
 P. T. Nelson, W. X. Wang, and B. W. Rajeev, “MicroRNAs
(miRNAs) in neurodegenerative diseases,” Brain Pathology,
vol. 18, no. 1, pp. 130–138, 2008.
 N. Patel, D. Hoang, N. Miller et al., “MicroRNAs can regulate
human APP levels,” Molecular Neurodegeneration, vol. 3, no. 1,
article 10, 2008.
 H. Fukumoto, B. S. Cheung, B. T. Hyman, and M. C. Irizarry,
in Alzheimer disease,” Archives of Neurology, vol. 59, no. 9, pp.
 R. M. D. Holsinger, C. A. McLean, K. Beyreuther, C. L.
Masters, and G. Evin, “Increased expression of the amyloid
precursor β-secretase in Alzheimer’s disease,” Annals of Neu-
rology, vol. 51, no. 6, pp. 783–786, 2002.
 P. Achard, A. Herr, D. C. Baulcombe, and N. P. Harberd,
“Modulation of floral development by a gibberellin-regulated
microRNA,” Development, vol. 131, no. 14, pp. 3357–3365,
 S. S. H´ ebert, K. Horr´ e, L. Nicola¨ ı et al., “MicroRNA regulation
of Alzheimer’s Amyloid precursor protein expression,” Neuro-
biology of Disease, vol. 33, no. 3, pp. 422–428, 2009.
dicer disrupts cellular and tissue morphogenesis in the cortex
and hippocampus,” Journal of Neuroscience, vol. 28, no. 17, pp.
 Y. Kawase-Koga, R. Low, G. Otaegi et al., “RNAase-III enzyme
Dicer maintains signaling pathways for differentiation and
survival in mouse cortical neural stem cells,” Journal of Cell
Science, vol. 123, no. 4, pp. 586–594, 2010.
 J. Bilen, N. Liu, B. G. Burnett, R. N. Pittman, and N.
M. Bonini, “MicroRNA pathways modulate polyglutamine-
induced neurodegeneration,” Molecular Cell, vol. 24, no. 1, pp.
 D. Shin, J. Y. Shin, M. T. McManus, L. J. Pt´ aˇ cek, and Y. H.
Fu, “Dicer ablation in oligodendrocytes provokes neuronal
impairment in mice,” Annals of Neurology, vol. 66, no. 6, pp.
6International Journal of Alzheimer’s Disease Download full-text
 W. Konopka, A. Kiryk, M. Novak et al., “MicroRNA loss
enhances learning and memory in mice,” Journal of Neuro-
science, vol. 30, no. 44, pp. 14835–14842, 2010.
 M. Fabbri, R. Garzon, A. Cimmino et al., “MicroRNA-
29 family reverts aberrant methylation in lung cancer by
targeting DNA methyltransferases 3A and 3B,” Proceedings
of the National Academy of Sciences of the United States of
America, vol. 104, no. 40, pp. 15805–15810, 2007.
 A. J. Kole, V. Swahari, S. M. Hammond, and M. Deshmukh,
“miR-29b is activated during neuronal maturation and targets
vol. 25, no. 2, pp. 125–130, 2011.
 X. Wang, P. Liu, H. Zhu et al., “miR-34a, a microRNA up-
regulated in a double transgenic mouse model of Alzheimer’s
disease, inhibits bcl2 translation,” Brain Research Bulletin, vol.
80, no. 4-5, pp. 268–273, 2009.
 W.-X. Wang, Q. Huang, Y. Hu, A. J. Stromberg, and P.
T. Nelson, “Patterns of microRNA expression in normal
and early Alzheimer’s disease human temporal cortex: white
2, pp. 193–205, 2011.
 Y. Zong, H. Wang, W. Dong et al., “miR-29c regulates BACE1
protein expression,” Brain Research, vol. 1395, pp. 108–115,
 N. Schonrock, Y. D. Ke, D. Humphreys et al., “Neuronal
microRNA deregulation in response to Alzheimer’s disease
amyloid-beta,” PloS One, vol. 5, no. 6, Article ID e11070, 2010.
 J. Yao, T. Hennessey, A. Flynt, E. Lai, M. Flint Beal, and M.
T. Lin, “MicroRNA-related cofilin abnormality in Alzheimer’s
disease,” PLoS One, vol. 5, no. 12, Article ID e15546, 2010.
 J. Shen and R. J. Kelleher, “The presenilin hypothe-
sis of Alzheimer’s disease: evidence for a loss-of-function
pathogenic mechanism,” Proceedings of the National Academy
of Sciences of the United States of America, vol. 104, no. 2, pp.
 A. M. Krichevsky, K. S. King, C. P. Donahue, K. Khrapko, and
K. S. Kosik, “A microRNA array reveals extensive regulation of
microRNAs during brain development,” RNA, vol. 9, no. 10,
pp. 1274–1281, 2003.
 L. Jing, Y. Jya, J. Lu et al., “MicroRNA-9 promotes differen-
tiation of mouse bone mesenchymal stem cells into neurons
by Notch signaling,” NeuroReport, vol. 22, no. 5, pp. 206–211,
 B. Bonev, A. Pisco, and N. Papalopulu, “MicroRNA-9 reveals
regional diversity of neural progenitors along the anterior-
posterior axis,” Developmental Cell, vol. 20, no. 1, pp. 19–32,
 Y. Y. Li, J. G. Cui, J. M. Hill, S. Bhattacharjee, Y. Zhao, and W.
J. Lukiw, “Increased expressionof miRNA-146a inAlzheimer’s
disease transgenic mouse models,” Neuroscience Letters, vol.
487, no. 1, pp. 94–98, 2011.
 W. J. Lukiw, Y. Zhao, and G. C. Jian, “An NF-κB-sensitive
micro RNA-146a-mediated inflammatory circuit in alzheimer
disease and instressedhuman brain cells,” Journalof Biological
Chemistry, vol. 283, no. 46, pp. 31315–31322, 2008.
 L. Li, X.-P. Chen, and Y.-J. Li, “MicroRNA-146a and human
disease,” Scandinavian Journal of Immunology, vol. 71, no. 4,
pp. 227–231, 2010.
 Y. J. Lee, S. B. Han, S. Y. Nam, K. W. Oh, and J. T.
Hong, “Inflammation and Alzheimer’s disease,” Archives of
Pharmacal Research, vol. 33, no. 10, pp. 1539–1556, 2010.
 S. W. Chi, J. B. Zang, A. Mele, and R. B. Darnell, “Argonaute
HITS-CLIP decodes microRNA-mRNA interaction maps,”
Nature, vol. 460, no. 7254, pp. 479–486, 2009.
 J. Vinther, M. M. Hedegaard, P. P. Gardner, J. S. Andersen,
and P. Arctander, “Identification of miRNA targets with stable
isotope labeling by amino acids in cell culture,” Nucleic Acids
Research, vol. 34, no. 16, article e107, 2006.
 L. P. Lim, N. C. Lau, P. Garrett-Engele et al., “Microarray
analysis shows that some microRNAs downregulate large
numbers of-target mRNAs,” Nature, vol. 433, no. 7027, pp.
 N. Patel, D. Hoang, N. Miller et al., “MicroRNAs can regulate
human APP levels,” Molecular Neurodegeneration, vol. 3, no. 1,
article 10, 2008.
 J. M. Long and D. K. Lahiri, “MicroRNA-101 downregulates
Alzheimer’s amyloid-β precursor protein levels in human
cell cultures and is differentially expressed,” Biochemical and
Biophysical Research Communications, vol. 404, no. 4, pp. 889–
 X. Fan, Y. Liu, J. Jiang et al., “MiR-20a promotes proliferation
and invasion by targeting APP in human ovarian cancer cells,”
Acta Biochimica et Biophysica Sinica, vol. 42, no. 5, pp. 318–
 E. Vilardo, C. Barbato, M. Ciotti, C. Cogoni, and F. Ruberti,
“MicroRNA-101 regulates amyloid precursor protein expres-
sion in hippocampal neurons,” Journal of Biological Chemistry,
vol. 285, no. 24, pp. 18344–18351, 2010.
 W. Liu, C. Liu, J. Zhu et al., “MicroRNA-16 targets amy-
loid precursor protein to potentially modulate Alzheimer’s-
associated pathogenesis in SAMP8 mice,” Neurobiology of
Aging. In press.
 T. O’Connor, K. R. Sadleir, E. Maus et al., “Phosphorylation of
the translation initiation factor eIF2α increases BACE1 levels
and promotes amyloidogenesis,” Neuron, vol. 60, no. 6, pp.
 V. Boissonneault, I. Plante, S. Rivest, and P. Provost,
“MicroRNA-298 and microRNA-328 regulate expression of
mouse β-amyloid precursor protein-converting enzyme 1,”
Journal of Biological Chemistry, vol. 284, no. 4, pp. 1971–1981,
 M. A. Faghihi, F. Modarresi, A. M. Khalil et al., “Expression
of a noncoding RNA is elevated in Alzheimer’s disease and
drives rapid feed-forward regulation of β-secretase,” Nature
Medicine, vol. 14, no. 7, pp. 723–730, 2008.
 J. Marksteiner, H. Hinterhuber, and C. Humpel, “Cere-
brospinal fluid biomarkers for diagnosis of Alzheimer’s dis-
ease: beta-amyloid(1-42), tau, phospho-tau-181 and total
protein,” Drugs of Today, vol. 43, no. 6, pp. 423–431, 2007.
 C. Reitz, C. Brayne, and R. Mayeux, “Epidemiology of
 M. Ciesla, K. Skrzypek, M. Kozakowska, A. Loboda, A.
onset,” Analytical and Bioanalytical Chemistry. In press.
 H. Mizuno, A. Nakamura, Y. Aoki et al., “Identification of
muscle-specific MicroRNAs in serum of muscular dystrophy
animal models: promising novel blood-based markers for
muscular dystrophy,” PLoS One, vol. 6, no. 3, Article ID
 K. Wang, S. Zhang, B. Marzolf et al., “Circulating microRNAs,
potential biomarkers for drug-induced liver injury,” Proceed-
ings of the National Academy of Sciences of the United States of
America, vol. 106, no. 11, pp. 4402–4407, 2009.