Title:Editorial (Thematic Issue: Overview of Immunotherapy in Alzheimer’s Disease (AD) and Mechanisms of IVIG Neuroprotection in Preclinical Models of AD)
Volume: 11
Issue: 7
Author(s): Scott E. Counts and Debomoy K. Lahiri
Affiliation:
摘要: Epidemiologic studies suggest that we are on the precipice
of a worldwide epidemic of Alzheimer’s disease (AD),
yet current treatment options are limited to short term symptomatic
relief. Recent advances in our knowledge of the neurobiology
of AD have resulted in the development of several
potential disease-modifying approaches based on immunotherapy.
The present special ‘Hot Topic’ (HT) issue of “Current
Alzheimer Research” deals primarily with the mechanisms
of passive vaccination with Intravenous Immunoglobulin
(IVIG), particularly within the context of neuroprotection
in preclinical models of AD. This HT issue is not
meant to report exhaustively on the many other research efforts
in the broader immunotherapy arena. Indeed, this journal
has recently covered various other aspects of immunotherapy
relevant to AD and related disorders. However, we
will briefly overview current immunotherapeutic strategies
for AD prior to discussing the main topic of IVIG neuroprotection.
One of the most significant approaches involves the removal
of brain amyloid-β peptide (Aβ) using anti-Aβ antibodies.
Aβ immunotherapy emerged as a promising treatment
strategy based on human neuropathology and preclinical
studies. The hallmark accumulation of parenchymal and
vascular Aβ pathology observed in the brains of AD subjects
suggested a logical target, and naturally occurring anti-Aβ
antibodies were found to be reduced in the cerebrospinal
fluid and blood of AD patients [1, 2]. In addition, both active
and passive amyloid immunization of AD transgenic mouse
models resulted in increased clearance of amyloid plaquelike
deposits and improved cognitive performance [3, 4],
whereas brain imaging and neuropathological studies suggested
the ability of both active and passive anti-Aβ immunotherapies
to clear Aβ deposits from the AD brain.
AN1792 was the first active immunotherapy strategy for
AD using full length Aβ42 as the immunogen; however, a
Phase II trial of this anti-amyloid vaccine was halted when
meningo-encephalitis appeared in a small subset of patients
[5]. Despite this setback, long-term follow-up of patients
immunized with AN1792 showed reduced functional decline
in antibody responders [6], supporting the hypothesis that Aβ
immunotherapy may have long-term functional benefits. In
this regard, novel Aβ immunogens with shorter peptide sequences
are in development which may avoid the autoimmune
responses to full length Aβ42 [7]. The first passive
anti-Aβ immunotherapy for AD focused on bapineuzumab.
Bapineuzumab, which is composed of humanized anti-Aβ
monoclonal antibodies, reduced Aβ burden in the brains of
AD patients in two Phase II trials. However, bapineuzumab
did not improve clinical outcomes in patients with AD, despite
treatment differences in biomarkers observed in APOE
ε4 carriers [8, 9]. Other recent approaches, such as systemic
co-administration of clioquinol and Aβ42 vaccines, significantly
reduce Aβ deposits in the brains of transgenic AD
mice [10]. In non-rodent models, a rapid improvement of
canine cognitive dysfunction with amyloid immunotherapy
suggests the important use of the canine model in testing
vaccines for AD [11]. So far, the limitations of Aβ-based
immunotherapy include the development of encephalitis, the
lack of clinical improvement, and the lack of effect on neurofibrillary
tangles (NFTs), another major neuropathological
feature of AD. Other critical points relate to the study design
and several variables in imunotherapy trials, which are essential
for optimizing trial designs and improving conditions
for participants [12].
Due to the central role of NFTs in dementia, immunotherapy
targeting these tau proteinous aggregates is an important
area of research [13, 14]. Notably, an active immunotherapy
targeting the tau pathological epitope phospho-
Ser422 was found to be efficient, resulting in tau clearance
and improved cognitive deficits promoted by tau pathology
in a well-defined tau transgenic model [15]. Like Aβ oligomers,
the putative role of tau oligomers in AD pathophysiology
has prompted an investigation into tau oligomers
as potential immunotherapeutic targets for AD and
tauopathies [16].
Taken together, these results suggest that immunotherapies
targeting Aβ alone may be insufficient for disease modification.
To this end, researchers also began testing whether
IVIG might serve as an alternative immunotherapeutic strategy.
IVIG is a mixture of naturally occurring human IgG
antibodies derived from the plasma of healthy young volunteers.
Notably, IVIG has been used for nearly half a century
for primary humoral immune deficiencies and autoimmune
syndromes and, more recently, a number of neurologic disorders
such as chronic inflammatory demyelinating polyradiculoneuropathy
and Guillain-Barré syndrome [17, 18].
The rationale for using IVIG for the treatment of AD
gained traction for a number of reasons. IVIG was found to
contain elevated levels of antibodies against multiple conformations of Aβ monomers and aggregates [19, 20], yet its
repertoire of naturally occurring antibodies might also be
predicted to normalize the inflammatory component of AD.
The safety profile of IVIG for other diseases also mitigated
concerns for AD clinical trials. Furthermore, if IVIG was
found to be beneficial in AD, the potential existed for identifying
treatment-specific antibodies to elucidate pathogenic
mechanisms and allow for more targeted therapeutic designs.
However, despite the initial promise of Phase I and II clinical
trials conducted in Germany and the US, a recent multicenter
double-blinded Phase III study of 390 subjects, called the
Gammaglobulin Alzheimer’s Partnership (GAP), did not
meet primary endpoints of slowing cognitive and functional
decline [21]. Then again, the GAP study results continued to
support IVIG’s positive safety profile and showed potentially
beneficial effects for pre-specified moderate AD and apoE4
carrier subgroups. Concurrent with these clinical trials, several
preclinical studies demonstrated that IVIG was neuroprotective
against Aβ toxicity in vitro and enhanced microglia-
mediated Aβ clearance ex vivo, whereas in vivo IVIG
delivery reduced inflammation in AD transgenic mice [22,
23]. Hence, the mechanism of action for IVIG is still of considerable
interest in the field and there remains the opportunity
for testing the extent to which optimized doses of IVIG
delivered early enough in the AD trajectory might yet prove
beneficial for modifying disease progression.
In the present HT issue, we summarize the state of the
field with respect to IVIG as a potential therapy for AD and
explore further the potential mechanisms of IVIG neuroprotection
in preclinical models of AD. Puli and colleagues review
our current understanding of the biologic and therapeutic
properties of IVIG relevant to AD therapy and highlight
their in vitro and in vivo studies on IVIG biological activities,
including the suppression of neuroinflammatory microglial
activation and concomitant increase in neurogenesis in
APP/PS1 mice [24]. Gong and colleagues expound upon
IVIG immunomodulatory mechanisms by showing that IVIG
regulates complement-derived anaphylatoxins, such as C5a
and C3, which in turn upregulates AMPA receptor-PKACREB
signaling pathways and improves synaptic function
and cognition in the Tg2576 mouse model of AD [25]. Lahiri
and Ray add to the diverse repertoire of IVIG neuroprotection
by reporting that treatment with IVIG protects neuronal
viability and synaptic proteins in primary rat hippocampal
neurons as well as in primary human brain cultures challenged
with oxidative stress, suggesting a potent neuropreservatory
effect of IVIG against oxidative insults [26]. In
addition, although IVIG has been reported to reduce amyloid
burden in some AD transgenic models, its potential effects
on tau NFT-like pathology in rodent models of disease are
unclear. Counts and colleagues show that IVIG reduces hippocampal
tau pathology in the 3xTg mouse model of AD
that exhibits NFT as well as plaque-like deposits. In addition,
this study reveals that IVIG preserves plasma levels of
mRNAs regulating neuronal cytoskeletal plasticity function
and calcium-mediated signaling compared to placebo [27]. It
is important to note that not all IVIG preclinical studies have
produced consistently positive results [28]. In this issue,
Joly-Amado and colleagues describe how four weeks of
IVIG infusion in Tg2576 mice led to widespread distribution
of human IgG in the forebrain, but had no effect on amyloid
burden or cognition [29]. However, the authors conclude by
agreeing that the beneficial effects of IVIG in mouse models
of AD are not likely due to its anti-Aβ antibody components
alone, but must also involve its wide range of antiinflammatory,
anti-oxidant, and other prosurvival and neuroprotective
properties. Hence, despite the negative topline
results from the GAP trial, these unique properties of IVIG
suggest that this polyclonal IgG mixture can potentially be a
safe and highly effective “top down” therapy for a complex
multifactorial disease like AD. Moreover, the data derived
from preclinical study designs may help guide current and
future IVIG clinical trials targeting early stage patients with
more optimized treatment regimens to prevent or delay the
onset of AD symptomology [30]. Finally, since efforts to
immunize against tau [31] and other AD-related targets have
been encouraging, these studies would potentially be excellent
subject matters for a future HT issue of the journal.
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