REVIEW ARTICLE
Animal models of amyloid-b-related pathologies in
Alzheimer’s disease
Ola Philipson
1
, Anna Lord
2
, Astrid Gumucio
1
, Paul O’Callaghan
1
, Lars Lannfelt
1
and Lars
N.G. Nilsson
1
1 Department of Public Health and Caring Sciences ⁄ Molecular Geriatrics, Uppsala University, Sweden
2 BioArctic Neuroscience AB, Stockholm, Sweden
Introduction
Alzheimer’s disease (AD) accounts for  60–70% of
all dementia cases. Prevalence increases with age from
 1% in the 60 to 64-year age group, to 24–33% in
those aged > 85 years. There is an insidious onset
with an initial loss of short-term memory, followed by
progressive impairment of multiple cognitive functions
that affect the activities of daily living. The AD diag-
nosis is based on a patient’s medical history, neurolog-
ical assessment and neuropsychiatric testing of
cognitive functions. Neuroimaging techniques and
biomarkers in cerebrospinal fluid (CSF) are invaluable
in differential diagnosis.

doi:10.1111/j.1742-4658.2010.07564.x
In the early 1990s, breakthrough discoveries on the genetics of Alzheimer’s
disease led to the identification of missense mutations in the amyloid-b
precursor protein gene. Research findings quickly followed, giving insights
into molecular pathogenesis and possibilities for the development of new
types of animal models. The complete toolbox of transgenic techniques,
including pronuclear oocyte injection and homologous recombination, has
been applied in the Alzheimer’s disease field, to produce overexpressors,
knockouts, knockins and regulatable transgenics. Transgenic models have
dramatically advanced our understanding of pathogenic mechanisms and
allowed therapeutic approaches to be tested. Following a brief introduction
to Alzheimer’s disease, various nontransgenic and transgenic animal models
are described in terms of their values and limitations with respect to patho-
genic, therapeutic and functional understandings of the human disease.
Abbreviations
AD, Alzheimer’s disease; ApoE, apolipoprotein E; APP, amyloid-b precursor protein; Ab, Amyloid-b; BACE-1, b-site APP cleaving enzyme-1;
CAA, cerebral amyloid angiopathy; CCR2, chemokine (C-C motif) receptor 2; CSF, cerebrospinal fluid; MWM, Morris water maze; NFTs,
neurofibrillary tangles; PDGF, platelet-derived growth factor; PS, presenilin; SMC, smooth muscle cells; wt, wild-type.
FEBS Journal 277 (2010) 1389–1409 ª 2010 The Authors Journal compilation ª 2010 FEBS 1389
lack b-sheet structure and are therefore by definition
not amyloid. Cerebral amyloid angiopathy (CAA)
results in the degeneration of vessel walls and hemor-
rhages. CAA is found in  80% of AD brains, but is
not a diagnostic criterion. NFTs are intracellular fila-
mentous lesions with amyloid properties. They contain
hyperphosphorylated and aggregated forms of tau, a
microtubule-associated protein that normally serves to
assemble and stabilize microtubules.
Genetics and risk factors implicated in
Alzheimer’s disease pathogenesis

AD neuropathology, and most experience dementia by
60–70 years of age [9].
The major genetic risk factor for developing late-
onset AD is the apolipoprotein E (ApoE) e4 allele
[10,11]. One ApoE e4 allele increases the risk of AD by
two- to threefold, and two e4 alleles confer a 12-fold
increase in risk. In the brain, ApoE is primarily synthe-
sized by astrocytes and serves to regulate the transport
of cholesterol-containing lipoprotein particles. ApoE
binds to Ab and becomes a component of amyloid in
AD senile plaques. The pathogenic mechanism of
ApoE likely relates to altered deposition and ⁄ or clear-
ance of Ab in the brain, although the details are still
not fully understood [12]. A large number of other dis-
ease-related loci and candidate genes have been pro-
posed, but not generally verified, indicating that these
genes have a modest impact on the pathogenesis. The
major risk factors for AD are age and a family history
of the disease. Low education or cognitive reserve
capacity, female gender, head trauma, hypertension,
cardiovascular disease and a high-cholesterol diet are
proposed risk factors for AD [13] (Fig. 2).
Nontransgenic animal models
Based on the cholinergic hypothesis, scopolamine-
induced amnesia, excitotoxic lesions of the basal
forebrain and aged primates have been used to assess
cognitive deficits. Current symptomatic drugs for AD
were successfully evaluated in these models, but their
etiological relevance is low [14]. Nontransgenic rodents
Fig. 1. Disease-causing APP mutations used in transgenic models. The Swedish mutation (1) favors b-secretase (b) cleavage, while the

tion, spatial disorientation and disturbed diurnal
rhythm. Cognitive dysfunction in old dogs is associated
with diffuse Ab deposits [20], neuritic dystrophy and gli-
osis, but few amyloid plaques and no NFTs. Ventricular
dilation, cortical and hippocampal atrophy, CAA with
degeneration of smooth muscle cells (SMC) and hemor-
rhages can all be found in aged canine brain. Interest in
nonhuman primate models has grown following the fail-
ure to predict meningoencephalitis as a side-effect of the
AN1792 vaccination trial from transgenic studies. The
efficacy and safety of an Ab vaccine has been tested in
the Carribean vervet monkey [21]. Alternatives are aged
lemurs [22], cotton-top tamarins [23], rhesus monkeys
[24] or squirrel monkeys [25]. An aged chimpanzee with
complete AD neuropathology, including neuritic
plaques and paired helical filament-containing NFTs,
was recently reported [26].
Fig. 2. AD pathogenesis according to the
amyloid cascade hypothesis. This theory
suggests that altered metabolism of Ab,in
particular aggregation-prone Ab species like
Ab42, initiates AD pathogenesis. Oligomeric
assemblies of Ab trigger aggregation of tau
and the formation of NFTs, but also inflam-
mation and oxidative stress, by rather
unclear mechanisms. These downstream
processes give rise to progressive neurode-
generation, which ultimately results in
dementia. The main pathogenic pathway of
AD is illustrated with red arrows, whereas

aggregates or amyloid deposists were found in the pan-
creas [28], intestine [29] or skeletal muscles [30]. The
level of plasma Ab in C99-based models was similar to
Tg2576, an APP transgenic model with high peripheral
promoter activity.
In an alternative strategy, a yeast artificial chromo-
some, harboring the whole APPwt gene, was used to
maintain transcriptional regulation, alternative splicing
and normal APP processing. In these Py8.9 mice,
proper APP protein synthesis and alternative splicing
was demonstrated, but the brain was devoid of neuro-
pathology and the levels of Ab were low [31]. How-
ever, when wild-type human APP was expressed at
very high levels, under the Thy1 promoter, sparse
parenchymal and vascular amyloid deposits were
found in aged mice [32]. Thus a pathogenic APP muta-
tion is not a prerequisite for amyloid deposition.
Instead it seems to depend upon producing sufficient
Ab levels in the brain to ensure fibrillization. To
explore the pathogenic impact of individual Ab spe-
cies, a fusion protein, BRI–wt-Ab42, was designed
from which Ab was released by furin-like enzymes on
the cell surface. BRI is a transmembrane protein that
is involved in amyloid deposition in British familial
dementia. The fusion design permitted the synthesis of
high Ab levels in the brain in a manner similar to APP
transgenic mice, but in the absence of APP overexpres-
sion. Transgenic mice expressing BRI–wt-Ab42 devel-
oped extensive vascular and parenchymal amyloid
pathology, accompanied by dystrophic neurites and

751
and APP
770
, with strong and
selective neuronal expression was enabled by the plate-
let derived growth factor (PDGF)b promoter. Impor-
tantly, young PDAPP mice produced high Ab42 levels
in the brain, particularly in the hippocampus. The ani-
mals preferentially accumulated Ab42 peptides and
developed senile plaques, but also a substantial num-
ber of diffuse Ab deposits at 9–10 months of age [37].
Plaque formation began in the cingulate cortex and
was accompanied by phospho-tau immunoreactive
dystrophic neurites, synaptic loss and gliosis in the
adjacent tissue, but not by overt neuronal loss [38,39].
Ultrastructural analyses revealed neurons in close
proximity to senile plaques and amyloid fibrils. The
latter had a diameter of 9–11 nm and were surrounded
by neuronal membranes and vesicles [40]. Young
PDAPP mice showed deficits in spatial learning and
memory, which worsened with increasing age and Ab
burden, although their performance in a novel
object-recognition task was unimpaired [41]. By
contrast, others found age-dependent deficits in object
recognition and place learning impairments that were
independent of age [42]. These discrepancies could be
because of differences in experimental procedures or
unintentional genetic drift of mouse colonies. PDAPP
mice are typically bred on a mixed genetic background
(Swiss Webster, DBA ⁄ 2 and C57Bl ⁄ 6). Hippocampal

extracts. Ab42 could still have initiated deposition of
Ab in vessels, because some focal lesions were only
Ab42-immunoreactive [45]. By contrast, brains from
patients with the London mutation contained mainly
Ab-immunoreactive plaques and cytoskeletal pathol-
ogy, but only modest or little CAA [46]. Thus, the
CAA phenotype in the transgenic mice might not have
been caused by the London mutation. Instead it may
be the result of strong APP expression, advanced age,
strain background (FVB ⁄ N) and ⁄ or differences in APP
processing between species.
Models with the Swedish APP mutation
The Swedish mutation (KM670 ⁄ 671NL) is located just
outside the N-terminus of the Ab domain in APP. It
was identified in 1992 [47] and shown to increase Ab
levels by six- to eightfold [4]. These discoveries created
intense interest in APP processing and paved the way
for the development of more sophisticated ELISAs to
selectively measure Ab40 and Ab42 [48]. Later, the
Swedish mutation became essential in the identification
and characterization of BACE-1 [49]. The clinical and
neuropathological features associated with the Swedish
mutation are those of typical AD [47,50]. Tg2576
mice, the most frequently used APP transgenic model,
harbor the Swedish mutation and display both AD-like
Ab neuropathology and cognitive deficits [51]. The
Swedish mutation redirects APP processing to secre-
tory vesicles en route to the cell surface in cell culture
[52], whereas APPwt is largely processed in recycling
endosomes [53]. This difference may be largely irrele-

around the murine Ab domain was replaced with the
human Ab sequence and the Swedish mutation. The
MoPrP.Xho vector was much smaller than the cos-
SHaPrP, and selectively directed twofold overexpres-
sion of APP to the brain [58,59]. In an even more
refined strategy, the murine Ab sequence was human-
ized and the Swedish mutation introduced with gene
targeting. In this knockin model, APP
NLh ⁄ NLh
, only
five single amino acids were altered in the entire mur-
ine genome. Consequently, APP protein synthesis
remained unchanged in terms of its spatial and tempo-
ral expression pattern and mRNA localization. The
Swedish mutation led to markedly enhanced b-secre-
tase activity and a ninefold increase in Ab level,
compared with normal aged human brain [60]. By
22 months of age, APP
NLh ⁄ NLh
mice had not devel-
oped Ab neuropathology [61], but young mice were
elegantly used to estimate the turnover of Ab, APP
and APP fragments in vivo [62]. In another genomic
approach, a 650 kb yeast artificial chromosome vector
harboring the whole human APP gene locus with the
O. Philipson et al. Animal models of Alzheimer’s disease
FEBS Journal 277 (2010) 1389–1409 ª 2010 The Authors Journal compilation ª 2010 FEBS 1393
Swedish mutation was used. In the homozygous mice
(R.1.40), in which Ab42 levels were 15 to 20-fold
higher than in mice expressing wild-type human APP,

mutations
Patients never inherit multiple pathogenic mutations in
APP, presenilin, tau or a-synuclein genes, nor do they
overexpress chimeric APP mRNA under a heterolo-
gous promoter. Thus none of the transgenic models
fully mimic the genetics of familial AD. By combining
genetic lesions one can accelerate Ab aggregation and
lower the cost of research. One can also confer certain
characteristics to Ab and dissect molecular interac-
tions. The Swedish mutation has often been used
together with other mutations in transgenic models
because it is located outside the Ab domain and serves
to enhance Ab levels.
No Ab pathology was evident at 24 months of age
in J.1.96 homozygous transgenic mice when a genomic
vector with both the Swedish and London mutations
was introduced, despite life-long exposure to a four- to
sixfold increased levels of Ab42, compared to human
APPwt [64]. In contrast, APP22 mice presented with
diffuse Ab deposits and few amyloid plaques when the
mutations were combined in a cDNA-strategy to
create twofold overexpression under the human Thy1
promoter [65].
The Tg-CRND8 model was designed by inserting
human APP
695
with Swedish and Indiana mutations in
the cosSHaPrP vector [55]. It resulted in an aggressive
neuropathology with onset of amyloid deposition and
place learning impairment as early as 3 months of age.

from  8 weeks of age, a consequence of 10 to 30-fold
increased APP expression and two pathogenic APP
mutations. APP transgene expression was suppressed
> 95% when 4-week-old mice were given doxycycline
for 2 weeks. Relative to doxycycline-free mice, Ab in
PBS- and SDS-soluble pools were efficiently cleared,
although Ab42 partially remained in the formic acid
soluble pool. By contrast, brains of animals reared on
doxycycline from birth to 6 weeks of age contained
essentially no human Ab, suggesting a very early onset
of Ab aggregation and a tightly controlled transgene
expression with little leakage. Interestingly, suppression
of the transgene in 6-month-old mice arrested amyloid
deposition, but did not promote clearance. Moreover,
astrogliosis and ubiquitin-positive dystrophic neurites
in the vicinity of senile plaques were unchanged. Thus,
the endogenous clearance systems were unable to
Animal models of Alzheimer’s disease O. Philipson et al.
1394 FEBS Journal 277 (2010) 1389–1409 ª 2010 The Authors Journal compilation ª 2010 FEBS
eliminate existing Ab aggregates and secondary pathol-
ogy, at least in this aggressive transgenic model [72].
Models with the Flemish, Arctic, Dutch or Iowa
APP mutation inside the Ab domain
Mutations at positions 21–23 in the Ab domain of
APP, near the hydrophobic cluster, are a heterogeneous
group of genetic lesions. They affect Ab aggregation
and degradation, but also APP processing. The Dutch
(E693Q) [73] and Iowa (D694N) [74] mutations are
associated with CAA and diffuse Ab deposits, resulting
in hemorrhagic strokes and ⁄ or infarcts and dementia.

The microvascular pathology was accompanied by
astro- and microgliosis as well as increased levels of
proinflammatory cytokines.
The Flemish (A692G) [78] mutation can start either
with presenile dementia or CAA. In contrast to the
other intra-Ab mutations, it makes APP an inferior
substrate for a-secretase and increases Ab levels
[79,80]. APP cleavage by b-secretase was favored in
transgenic mice with the Flemish mutation (APP ⁄ Fl),
with modestly increased Ab1-40 levels. There was
spongiosis and gliosis in APP ⁄ Fl mice, but no Ab or
tau pathology. Male APP ⁄ Fl mice, which were bred on
the FVB background, were aggressive and suffered
premature death and seizures. APP expression was
likely insufficient to generate neuropathology and it is
unclear if the findings in APP ⁄ Fl were specifically
caused by the Flemish mutation. An APP ⁄ Du model,
developed in parallel, displayed similar phenotypes
[81].
The Arctic APP mutation (E693G) [79] is associated
with clinical features of early-onset AD commencing at
52–62 years. There are NFTs, severe CAA in the
absence of hemorrhage and an abundance of paren-
chymal Ab deposits lacking amyloid cores in postmor-
tem brain [82]. The Arctic mutation promotes Ab
protofibril and fibril formation, but also favors intra-
cellular b-secretase processing of APP [79,83,84].
Tg-ArcSwe models with both the Swedish and Arctic
mutation were developed by two independent groups.
In young mice, the Arctic mutation increased intraneu-

mice, amyloid deposition was markedly accelerated in
O. Philipson et al. Animal models of Alzheimer’s disease
FEBS Journal 277 (2010) 1389–1409 ª 2010 The Authors Journal compilation ª 2010 FEBS 1395
bigenic PS-1 · APP transgenic mice [91,92]. Borchelt
et al. generated PS-1 transgenic models expressing
mutant protein (M146L, A246E or PS1DE9), which
were cross-bred with APP transgenic mice with the
Swedish mutation, line C3-3 [58,91]. Other researchers
cross-bred Tg2576 with PS-1 transgenic mice, in which
PS-1 cDNA (M146L or M146V) had been linked to
the PDGFb2 promoter [90], resulting in the PSAPP
model [92]. PS2APP mice, generated by crossing PS2
(N141I) and APP-Swe, also displayed an aggressive
Ab pathology with age-dependent spatial learning and
memory deficits [93].
Autosomal dominant mutations in tau causing
frontotemporal lobe dementia were quickly utilized for
transgenic experiments. The JNPL3 model, expressing
4R0N tau isoform with the P301L mutation, was the
first model with Gallyas-positive NFTs. When double-
transgenic mice were created by cross-breeding with
Tg2576 a more complete AD neuropathology was
generated. Moreover tau pathology, but not Ab patho-
logy, was enhanced in these mice, suggesting that effects
on tau are downstream of Ab in AD pathogenesis [94]
(Fig. 2). However triple-transgenic mice, which were
generated by crossing mice producing the wild-type tau
isoform (3R0N) with mice carrying the Swedish and
London APP mutations and a PS-1 mutation (M146L),
only resulted in somadendritic accumulation of tau and

in 12 to 15-month-old mice, whereas paired helical
filament-1 immunoreactivity and Gallyas staining,
which indicate NFT formation, were not seen until
18 months of age [98]. In more recent studies of this
model, amyloid deposition commenced at  15 months
in the hippocampus and was widespread > 18 months
[99]. Triple-transgenic mice have been elegantly used to
study interactions between Ab and tau pathologies and
their impact on phenotypes of synaptic and cognitive
dysfunction [100,101].
Advanced animal models have recently been gener-
ated in which neuronal degeneration is clearly evident.
In the 5xFAD transgenic model, Thy1 promoter-driven
transgenes of APP (with the Swedish, Florida and
London AD mutations) and PS-1 (with the AD muta-
tions M146L and L286V) were coinjected into pronu-
clei of C57BL ⁄ 6xSJL mice. The model was made in an
effort to alter the Ab42 ⁄ Ab40 ratio in favor of Ab42
synthesis ([102] and references therein). Indeed the
strategy resulted in a high level of Ab42 and an
Ab42 ⁄ Ab40 synthesis ratio of 25 : 1 in young mice, in
comparison with 0.1–0.2 : 1 in Tg2576 mice with only
the Swedish APP mutation. Amyloid deposits formed
within 2 months, and the mice also developed intran-
euronal Ab aggregates. The intraneuronal deposits
were in a b-pleated sheet conformation, and located to
large pyramidal neurons of cerebral cortex layer V.
Interestingly, in 9-month-old 5xFAD-mice there was a
selective loss of these neurons and a decrease of several
synaptic markers. Importantly, these phenotypes and

CSF
⁄ [Ab]
plasma
should be the same in all trans-
genic models. A much higher plasma Ab level in
Tg2576 mice than in APP23, but a comparable
central nervous system Ab level, is inconsistent with
the idea of a dynamic equilibrium. The higher plasma
Ab levels in Tg2576 is most likely explained by the
stronger peripheral activity of the hamster PrP
promoter, compared with the neuron-specific Thy1
promoter in APP23. This emphasises the influence of
promoter selection on differential expression patterns
of APP and steady-state Ab levels in the central
nervous system and in peripheral tissue; consequently,
interpretations from transgenic models regarding Ab
dynamics should be made with caution.
In the 1980s it was debated whether Ab amyloid
deposits, and in particular CAA at the cerebral vessel
wall, had a central nervous system or a peripheral
source. Models driven by the Thy1 promoter, like
APPDutch transgenic mice, with almost exclusive
neuronal central nervous system expression of APP
develop almost only CAA, but by introducing a
presenilin transgene and raising the ratio of
Ab42 ⁄ Ab40 synthesis instead mainly parenchymal
senile plaques develop [32]. By contrast, models with
peripheral APP synthesis and high plasma Ab levels
present with amyloid deposits in peripheral organs
and neither CAA nor Ab plaques are found in the

1–40
. A density 1 gÆL
)1
for brain tissue has been assumed when the ratio of brain Ab ⁄ plasma Ab
has been calculated. Thus, for example, 20 pmolÆg
)1
 20 nM. Studies on the initial description and on metabolic levels of brain, CSF and plasma Ab that were used as sources of informa-
tion are cited. APP, amyloid-b precursor protein; CAA, cerebral amyloid angiopathy; NFT, neurofibrillary tangles; PDGF, platelet-derived growth factor.
Model Transgene Promoter Neuropathology
Age-of
-onset
(months)
Brain
Ab
(pmolÆg
)1
)
Plasma
Ab
Ratio
brain Ab ⁄
plasma Ab
CSF
Ab
Ratio
brain Ab ⁄
CSF Ab Contact
PDAPP [36,37,105] APP minigene V717F
(Indiana)
PDGF Diffuse and neuritic

CAA NFTs, atrophy
20 90 p
M 220 1.6 nM 12
O. Philipson et al. Animal models of Alzheimer’s disease
FEBS Journal 277 (2010) 1389–1409 ª 2010 The Authors Journal compilation ª 2010 FEBS 1397
formed very rapidly, within 1–2 days, reaching a size
that was surprisingly stable. Within 1 week, early
changes were accompanied by the recruitment of
reactive microglia, and shortly thereafter by neuritic
dystrophy [113]. However, in a subsequent study,
plaque growth occurred over a period of weeks when a
thinned-skull cranial window was used instead [114].
There is also a local neurotoxic effect on nerve endings
near amyloid plaques in APP transgenic models and in
AD postmortem brain [115], whereby dendritic spines
decrease in density but do not change in structure
[116]. Loss of CA1 pyramidal neurons in the hippo-
campus was reported in aged APP23 mice with a high
plaque load [117], although subtle cell loss is difficult
to distinguish from physical displacement. Today,
almost every research article in the AD field contains
an introductory statement in which the neurotoxicity
of Ab is described as a well-established fact, yet analy-
ses of mouse brain in which large amounts of Ab have
accumulated provide no or very sparse support for this
hypothesis. Neurodegenerative mechanisms of proteop-
athies are still largely unknown. Perhaps the neurotox-
icity is sparse because APP trafficking and subcellular
Ab accumulation in AD brain is poorly mimicked in
most models, as chimeric APP mRNAs are overexpres-

expressed under the glial fibrillary acidic protein
promoter in PDAPP mice lacking murine ApoE.Ab
burden was then accelerated by the risk allele ApoE e4
and decelerated by the protective allele ApoE e2, rela-
tive to the ApoE e3 allele [120]. These findings fit well
with observations in postmortem AD brain [121].
However, although murine ApoE facilitates Ab deposi-
tion in a gene-dose-dependent manner, human ApoE
decelerates Ab deposition compared with murine
ApoE [122]. This may be because a human transgene
was introduced into a complex feedback network
involving murine lipoprotein receptors. Alternatively,
ApoE may affect both Ab clearance and deposition. It
illustrates the complexity of detailed mechanistic stud-
ies. Deletion of apolipoprotein J, which also binds to
Ab, decelerated amyloid formation [123], whereas abla-
tion of both ApoE and apolipoprotein J strongly
increased Ab deposition [124]. Possibly the lipoprotein
metabolism in the brain is altered when two abun-
dantly expressed apolipoproteins, E and J, are both
absent. Lipidation of ApoE-containing lipoparticles via
the ATP-binding cassette family of active transporters
regulates Ab deposition. PDAPP mice overexpressing
murine ATP-binding cassette family of active transport-
ers 1 are phenotypically similar to those devoid of
murine ApoE. In contrast, Ab and amyloid deposition
is accelerated in APP transgenic mice devoid of ATP-
binding cassette family of active transporters 1 ([12] and
references therein).
Neuroinflammation has been suggested to influence

play a role in Ab biology,
and possibly in AD pathogenesis. Both ions bind APP
and Ab with high affinity, and stimulate Ab aggrega-
tion and oxidizing effects of Ab in vitro. By deleting
the gene encoding a zinc transporter, ZnT3, the endog-
enous pool of synaptic Zn
2+
was depleted. Senile
plaque deposition was then markedly decelerated in
Tg2576 mice in a dose-dependent manner, whereas
soluble Ab was modestly increased. Synaptic zinc and
ZnT3 changed in response to ovariectomy and estro-
gen replacement possibly explaining why increased Ab
burden is often observed in female APP transgenic
mice [57,135,136].
As described above, knowledge on pathogenic
mechanisms has often been gained by removing or
expressing normal or mutant genes and examining
APP ⁄ Ab-related phenotypes. A major caveat when
interpreting the results from a cross-breeding experi-
ment is the influence of the genetic background. This
problem can be circumvented by expressing a trans-
gene at a specific location in the brain with a lentiviral
vector [137]. The relevance of cross-breeding experi-
ments is strengthened if expression and deletion of the
gene(s) results in the opposite outcome, or if the results
are substantiated by in vitro studies or analyses of
clinical samples. The ability to track pathogenic events
in living animals with intravital multiphoton micros-
copy, small animal PET cameras and microdialysis

placebo-treated groups can then lead to a systematic
error that is mistakenly interpreted as evidence of ther-
apeutic efficacy. Many APP transgenic models also
suffer spontaneous death, which drives selection in a
cohort of animals by unknown mechanisms. Conse-
quently, a drug under investigation might modulate
spontaneous death and not AD-pathogenesis. Ran-
domizing experimental groups, matching them for gen-
der, and having sufficient power are therefore
extremely important in minimizing the influence of
confounding factors arising from inherent problems
associated with breeding APP transgenic mice and
maintaining stable phenotypes. We would argue that a
single report that has not been replicated, preferably
by other researchers, provides weak evidence of thera-
peutic efficacy.
Knowledge of the pathway one intends to target
and the pharmacological mechanism of the drug are
equally important. In vitro and in vivo pharmacology
of the drug should preferably be carried out before
efficacy is tested in APP transgenic mice. Unfortu-
nately, many drug candidates or dietary supplements
are simply directly tested for in vivo efficacy in the
absence of prior pharmacological and pharmacoki-
netic experiments, and without mechanistic knowl-
edge. One also needs to carefully consider which
transgenes to express ⁄ suppress and what pathogenic
AD mutation to include in the animal model. For
example, a putative BACE-1 inhibitor can be evalu-
ated in a transgenic model with the Swedish mutation

nately, in a clinical trial AD patients (and likely some
healthy subjects) will have substantial amounts of Ab
and tau pathology at the commencement of treatment.
Protein aggregation has often only been prevented in
APP transgenic mice, but it is far more difficult to
clear existing Ab deposits. This has also been seen in,
for example, superoxide dismutase 1 transgenic mice
models of amyotrophic lateral sclerosis [141]. There-
fore, to avoid overinterpreting therapeutic studies in
transgenic mice, it is important to record the age and
evaluate the stage of neuropathology when the animals
were first given the drug. Here we present a few exam-
ples of Ab-based drug candidates that are in preclinical
or clinical development.
Ab immunotherapy is perhaps the most promising
disease-modifying treatment strategy for AD, and it
also illustrates the potential clinical value of transgenic
mice. Immunization would probably never have been
pursued if APP transgenic mice had not been avail-
able. Human clinical trials of active immunization with
fibrillar Ab
1–42
(AN1792) were rapidly initiated when
biochemical and functional efficacy had been proven in
APP transgenic mice [142–144]. Studies were halted in
phase II, because meningoencephalitis developed in a
subgroup of patients [145]. Encouragingly, there was
evidence of Ab plaque clearance in postmortem brain
of vaccinated patients, resembling that of transgenic
mice [146]. Passive immunization, i.e. direct adminis-

and providing suggestive biomarkers to be used in
clinical trials. Examples of pioneering studies are the
demonstration of impaired remyelination of sciatic
nerves and reduced cleavage of the neuregulin-1 pre-
cursor in BACE-1 knockout mice [154], and lethal phe-
notypes observed in PS-1 knockout mice. The latter
experiments led to the realization that the c-secretase
complex also regulates the Notch cell signaling
pathway [155].
Functional studies with AD models
We regard behavioral studies with APP transgenic
mice as being relevant to prove that a certain Ab
species or a pathological lesion has a functional effect
on neurotransmission. Because our knowledge of the
mechanisms and neuropathology of AD are both
incomplete, it is not possible to predict if a new
drug will impact on AD symptomatology based on
functional studies with APP transgenic mice.
Effects of the promoter, transgene overexpression
and strain background all need to be considered when
interpreting functional studies. These parameters can
have a major impact on behavior and also generate
variability. It is also difficult to distinguish between
deficits caused by Ab or APP overexpression. A trans-
genic model should ideally first be investigated in a
comprehensive battery of cognitive and sensorimotor
tests [156], which is labor intensive but can be reward-
ing if combined with statistical analyses [157]. The
MWM task is one of the most widely used cognitive
tests. It depends on hippocampal formation, which is

drawbacks and limit variability associated with
conventional behavioral tasks. These systems should
facilitate reproducible functional studies with animal
models of AD.
Concluding remarks and future
perspectives
Transgenic techniques have revolutionized our ability
to develop animal models of AD, and also contributed
significantly to the understanding of molecular patho-
genesis. Today a wide range of animal models are
available for mechanistic, therapeutic and functional
studies. They offer an appealing means to rapidly
move from simplistic in vitro experiments to clinical
trials. It is important to understand the strengths and
limitations of the models (Table 2). We foresee that
technical advances in RNA interference and gene tar-
geting with, for example, zinc-finger nucleases will be
increasingly utilized in the future. This could lead to
new animal models of AD where proteins are not
overexpressed and also to more sophisticated studies
of pathogenic mechanisms in APP transgenic mice.
Moreover, chimeric proteins will frequently be
designed to target transgene expression to certain sub-
cellular locations in postmitotic neurons and to then
express only a defined Ab peptide. The first transgenic
nonhuman primate model of AD will be developed, as
a result of recent successes in modeling Huntington’s
disease [163]. This will enable limited therapeutic stud-
ies where effects of a new drug on higher cognitive
functions can be better evaluated with high-resolution

C3-3 [58] 18 + + nr nr + ) nr
R.1.40 [64] 14 +++ +++ + nr )) nr
APP23 [65] 6 +++ + + nr +++ ) nr
Tg-CRND8 [69] 3 +++ + + nr + ) nr
APPDutch [32] 22–25 ) + +++ + +++ ) nr
SweDI [75] 3 ) +++ +++ nr +++ ) nr
Tg-ArcSwe [86] 6 +++ + + +++ +++ ) nr
APParc [89] > 12 + + + ) +++ ) nr
PSAPP [92] 6 +++ + + nr + ) nr
3xTg-AD [98] 6 +++ +++ + +++ +++ ) nr
5xFAD [102] 2 +++ + nr +++ +++ + nr
APP ⁄ PS1 KI [104] 2–3 +++ + nr +++ +++ + +++
TBA2 [118] 2 nr +++ ) +++ +++ +++ +++
O. Philipson et al. Animal models of Alzheimer’s disease
FEBS Journal 277 (2010) 1389–1409 ª 2010 The Authors Journal compilation ª 2010 FEBS 1401
careful in vitro experiments and advanced early clinical
studies will provide important contributions to the
development of the first approved disease-modifying
drug for AD.
Acknowledgements
Mattias Staufenbiel and Thomas Bayer are greatly
acknowledged for providing information on the
APP23 and TBA ⁄ 2 models, and the Swedish Research
Council (2009-4567, LL; 2009-4389, LN) provided
financial support.
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