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The global burden of Alzheimer disease (AD), already abnormalities and AD pathogenesis in the brain. We
the most common type of dementia, is expected to review emerging findings of associations between sys-
increase still further owing to population ageing. AD not temic abnormalities and A metabolism, and describe
only causes severe distress for patients and caregivers, how these associations might interact with or reflect on
but also results in a large economic burden on society. the central pathways of A production and clearance.
Current major challenges in AD include the lack of reli- On the basis of these findings, we suggest that inter
able biomarkers for its early diagnosis, as well as the lack actions between the brain and the periphery might have
of effective preventive strategies and treatments1,2. Thus, a crucial role in the development and progression ofAD.
increased understanding of the molecular pathogenesis
1
Department of Neurology of AD could lead to the development of improved A biogenesis and catabolism
and Centre for Clinical
diagnostic and therapeutic strategies. A steady accrual of data from laboratories and clinics
Neuroscience, Daping
Hospital, Third Military AD is conventionally regarded as a CNS disorder. is providing increasing support for the concept that an
Medical University, However, increasing experimental, epidemiological and imbalance between the production and clearance of A is
10 Changjiang branch road, clinical evidence has suggested that manifestations of a very early (and often initiating) factor in AD3. Normal
Daping, Chongqing, 400042, AD extend beyond the brain. These systemic alterations metabolism of A and maintenance of the homeostatic
China.
2
The Florey Institute,
might not be simply secondary effects of the cerebral balance between A production and clearance is, there-
The University of Melbourne, degeneration seen in AD, but could reflect underlying fore, essential to maintain brain health. Infact, physio-
30 Royal Parade, Parkville, processes linked to progression of the disease. AD logical metabolism of A occurs not only in the brain
Victoria 3052, Australia. pathogenesis is complex, involving abnormal amyloid- but also in the periphery, and c ommunication between
*These authors contributed
(A) metabolism, tau hyperphosphorylation, oxidative these regions is possible (FIG.1).
equally to this work.
stress, reactive glial and microglial changes, and other
Correspondence to
Y.-J.W.and C.L.M.
pathological events. Given that A is a major hallmark Central and peripheral production of A
yanjiang_wang@tmmu.edu.cn; of AD and a fertile area of research in this disease, this A is derived from the proteolytic cleavage of amyloid
c.masters@florey.edu.au Review focuses on the systemic role of A in AD. We dis- precursor protein (APP), which is expressed not only in
doi:10.1038/nrneurol.2017.111 cuss the communication between peripheral and central brain cells, including neurons, astrocytes and microglia,
Published online 29 Sep 2017 pools of A, and describe interactions between systemic but also in peripheral organs and tissues, such as the
Brain
A production A clearance
CNS clearance
Neuron
CNS pool
A in ISF A in CSF
Astrocyte
A Aggregation and deposition
(mainly A42)
CSF absorption clearance
BBB clearance (arachnoid villi, BCSFB,
(LRP1, P-glycoprotein, etc) lymphatic pathway)
Microglia
Inux Eux
Blood
A production A clearance
BBB entrance
(RAGE)
Degradation clearance
(phagocytosis by blood
cells and degradation
Monocytes Neutrophils A-degrading by enzymes)
enzymes
Blood ow clearance
A (by RBCs, lipoproteins,
(mainly A42) albumin, etc)
Peripheral clearance
RBC Lipoproteins Albumin
Peripheral pool
Platelets
Osteoblasts
Figure 1 | Physiological metabolism of A in the brain and periphery. Amyloid (A) is generated by neurons,
Nature Reviews | Neurology
microglia and astrocytes in the brain, and by platelets, skin fibroblasts, osteoblasts, and skeletal muscle cells in the
periphery. The CNS and peripheral pools of A can interact; some A peptides in the CNS are cleared via phagocytosis or
proteolytic degradation, whereas others are released into the blood via the bloodbrain barrier (BBB), interstitial fluid (ISF)
bulk flow or cerebrospinal fluid (CSF) egress pathways. Some A peptides in blood are phagocytosed, including by
monocytes or neutrophils, some are degraded by A-degrading enzymes, and some are transported by carriers (such as
erythrocytes, albumin and lipoproteins) to peripheral organs or tissues, where they are degraded by macrophages or
hepatocytes, or excreted via the liver or kidney. BCSFB, bloodCSF barrier; RAGE, receptor for advanced glycation end
products; RBC, red blood cell.
Communication between A pools BBB, including LDL-related protein1 (LRP1) and ATP-
Brain-derived A can be transported into the periph- dependent efflux transporter P-glycoprotein29. The
eral pool via the BBB, bloodCSF barrier, arachnoid arachnoid villi absorb A in the CSF and mediate its
villi or glymphaticlymphatic pathway. Several trans- release into the circulation30. The glymphaticlymphatic
porters mediate A flow out of the brain across the pathway, which consists of the glymphatic pathway in
Table 1 | Amounts of A in the CNS and periphery processes in the AD brain can also drive these systemic
disorders, forming feedback loops. Mechanisms that
Source of A Cognitively normal Patients with Alzheimer Refs might underlie the effects of systemic abnormalities or
elderly individuals disease
alterations on A metabolism are outlined in TABLE2.
Brain grey matter Here, we discuss the interactions between A metabo
Total A* 3.2g/g 13.1g/g 5,168 lism in the brain and periphery, and place them in a
systemic context.
A40 0.2g/g 0.6g/g 5
A42 0.78g/g 6.1g/g 5 Disorders of systemic immunity
Packed quiescent platelets One of the primary pathways of A clearance in the
84.0ng/ml Not available 5
brain is phagocytosis or endocytosis by professional
A40
phagocytes and microglia, as well as by astrocytes,
A42 1.7ng/ml Not available 5 oligodendrocytes and neurons. Accumulations of
Packed activated platelets A in the periphery can similarly be phagocytosed
A40 56.8ng/ml Not available 5 by monocytes and neutrophils in the blood, and by
macrophages in tissues41. Of note, in transgenic mice
A42 1.6ng/ml Not available 5 with AD, expression of A scavenger receptors and
Skeletal muscle Adegrading enzymes in circulating mononuclear
A40 29.8ng/g 37.8ng/g 5 phagocytes decreases substantially as these mice age42,
and the phagocytic functions of these cells are impaired
A42 10.2ng/g 15.7ng/g 5
in both mice and humans with AD4345. Infusion of
*Includes A40, A42 and shorter peptides (An40, An42).Suggested to be the primary source of monocytes derived from peripheral human umbilical
soluble A (which is mainly A40) in the circulation169,170. A might also be generated by skin
fibroblasts and osteoblasts5,171173, although these findings have not yet been confirmed. cord blood reduces the A burden and improves cog-
A,amyloid. nitive deficits in a mouse model of AD46, implying that
peripheral mononuclear phagocytes have an important
role in A clearance. Promoting the phagocytic func-
the brain and the CNS lymphatic vessels (discovered in tion of peripheral blood monocytes or promoting the
2015)31,32, might also transport A from the brain to the recruitment of peripheral macrophages into the brain
periphery for clearance18,33. However, the glymphatic might, therefore, improve A clearance in the brain47,
lymphatic pathway and arachnoid villi are unidirec- although the existence of conflicting data48 renders this
tional; they only mediate A efflux from the CNS to approach controversial.
theperiphery 18. In this regard, a cluster of genes associated with the
Whether peripherally generated A can enter the risk of sporadic AD (including CD33, CR1, MS4A6A,
brain and exert neurotoxic effects there remains poorly MS4A4E, ABCA7 and TREM2)49,50 encode proteins that
understood. In the absence of a relevant transport are involved in innate immunity. Variants in these genes,
mechanism, systemic amyloidosis might not neces especially in TREM2 and CD33, are associated with
sarily lead to AD. However, peripheral inoculation compromised phagocytic function of peripheral mono-
of Acontaining brain extracts induces cerebral A cytes or macrophages and altered A accumulation in
deposition in both mice and humans, suggesting that AD brains24,51. Interestingly, CR1 (encoding complement
peripherally generated A is able to enter the brain and receptor1, also known as CD35) is expressed primarily
participate in the pathogenesis of AD3437. Receptor for in peripheral leukocytes and erythrocytes, but not in any
advanced glycation end products (RAGE) has been sug- braincells.
gested to transport A across the BBB, from the blood In regard to adaptive immunity, much attention
into the brain38. Expression of the AGER gene (encoding has been focused on autoimmunity and autoreactive
RAGE) is upregulated in the AD brain vasculature39,40, antibodies related to the pathogenesis of AD, includ-
indicating that influx of peripheral A into the brain ing naturally occurring antibodies and autoantibodies.
is increased in AD. The contribution of peripherally These autoreactive antibodies are ubiquitous in human
derived A to amyloidosis in the AD brain needs to be blood and CSF, and profiles of these antibodies are
determined in future studies. altered in patients with AD5256. Identification of the
A decline in peripheral A clearance might also most antigenic epitopes targeted by human antibodies
impede efflux of A from the brain to the periphery, against A aggregates could lead to development of an
and thereby attenuate central clearance of A. Moreover, effective immunotherapy for AD. Aducanumab, derived
the influx and efflux of A might result in equilib- from a naturally occurring human autoantibody against
rium between the central and peripheral pools of A. Cu 2+modified A aggregates (which are the most
Mechanisms that might regulate this equilibrium need neurotoxic A species in the AD brain), showed prom-
to be understood. ise in clearing brain A deposits and improving cogni-
tion in a 2016 phaseIb trial57. Lymphocytes (including
Systemic abnormalities in AD Bcells, Tcells and natural killer cells) also participate
An increasing number of studies indicate that a series in A clearance via immunoglobulin-mediated adaptive
of systemic abnormalities can exacerbate the progres- phagocytosis58,59. Future studies will help to elucidate
sion of AD (FIG.2). In turn, the downstream effects of the crosstalk between innate immunity and adaptive
Figure 2 | Systemic abnormalities in AD. Various systemic abnormalities have been found in patients with Alzheimer
Nature Reviews | Neurology
disease (AD). Red boxes highlight AD risk variants in genes related to innate immunity, phagocytosis of amyoid- (A)
byimmune cells, and lipid metabolism in periphery and brain, respectively, which were identified in genome-wide
association studies and candidate-gene studies of sporadic AD. APP, amyloid precursor protein; BA, basilar artery; COPD,
chronic obstructive pulmonary disease; CRP, Creactive protein; HDL-C, HDL-cholesterol; IGF, insulin-like growth factor;
LDL-C, LDL-cholesterol; LPS, lipopolysaccharide; LTICA, left terminal internal carotid artery; OSA, obstructive sleep
apnoea; PI, pulsatility index; RBC, red blood cells; RI, resistance index; RTICA, right terminal internal carotid artery;
TNF,tumour necrosis factor.
immunity, and to discover how the interaction of identification of these protective components could be
these two immune systems might synergistically affect of importance in understanding the pathogenesis of AD
ADpathogenesis. and in developing systemic rejuvenation therapies6871.
Compared with healthy control individuals, patients associated with a reduced risk of AD136. These findings
with OSA or chronic obstructive pulmonary disease suggest that chronic systemic inflammation promotes
exhibit higher blood levels of A, which negatively the AD process.
correlate with pulmonary function121,122. OSA is also By contrast, acute systemic inflammatory responses
associated with altered levels of AD biomarkers in CSF, seem to protect against AD at least in animal models
including decreased levels of A42 and elevated levels by recruiting monocyte-derived macrophages into
of phosphorylated tau123. OSA and chronic obstructive the brain, where they clear cerebral A47. However,
pulmonary disease could contribute to AD processes most studies in this area have not been repeated, and
via hypoxia, inflammation, or sleep disruption124. Sleep their results have not yet been validated in patients with
disruption has been suggested to increase A produc- biomarker-confirmedAD.
tion and aggregation, suppress glymphatic clearance
of AD pathogenic proteins (tau as well as A) and A systemic approach to understanding AD
aggravate oxidative stress, inflammation and synaptic The close interaction between the brain and the
damage125,126. periphery, in terms of A metabolism, provides novel
insights into the pathogenesis of AD, and could lead to
Gut microbiota disturbance and infection new approaches to the diagnosis and treatment of AD,
The establishment of the gutbrain axis revealed a clear based on systems biology and systems neurophysiology
association between the gastrointestinal microbiota and paradigms.
cognition127. Gram-negative bacterial species (such as
Escherichia coli K99) are the predominant sources of Pathogenesis
bacteria-derived factors in normal human brains, and Our current understanding of the role of A in AD
levels of these molecules are increased in AD brains, along focuses on its contribution to brain pathology and symp-
with levels of the bacterial cell wall component lipopoly- toms. However, as already discussed, this view might
saccharide128. Lipopolysaccharide colocalizes with A in not be the whole story. First, although A peptides are
plaques in AD brains128, suggesting that Gram-negative generated in the brain, a considerable amount of A is
bacteria are associated with AD pathogenesis. Probiotic also generated in peripheral systems. Second, A can be
supplementation is associated with improved cognition cleared from peripheral organs or tissues as well as
in patients with AD129, which further supports a role for from the brain by professional phagocytes, which can
the gut microbiota in AD development. transmigrate through the BBB. Third, A deposits have
In addition to its relationship with normal microbial been detected in the periphery although this claim
flora, emerging evidence indicates that AD is associ has not yet been replicated and its pathophysiological
ated with exposure to an ever-increasing number of relevance remains unknown. Last, a series of systemic
pathogens130,131. Moreover, a high infectious burden is abnormalities are both driven by and contribute to AD
associated with increased serum levels of A and pro progression. On the basis of these findings, we propose
inflammatory cytokines in patients with AD and in that AD might not be solely a brain disorder, in the sense
healthy controls130. However, the underlying mechanisms that systemic factors might interact with the brain to
through which the microbiota or pathogens influence modify the AD process.
AD remain to be determined. Whether the microbiota As discussed, the central and peripheral A pools
or pathogens contribute to AD development, or whether interact with and influence each other. For exam-
an increased infectious burden is a c onsequence of AD, ple,therate of peripheral catabolism of A seems to
also remains unknown. affect the rate of A efflux from the brain, and periph-
erally derived A can enter the brain and accelerate the
Systemic inflammation progression of cerebral AD pathology 34,35. Therefore, we
Chronic reactive gliosis and microgliosis are neuro hypothesize that the peripheral pool of A is not simply
inflammatory responses that are important contributors associated with AD, but is causally linked to this disease.
to AD pathology. These processes might participate in Indeed, interactions between the brain and the periphery
a positive feedback loop of A deposition, neurofibril- might have a crucial role in the natural history of AD,
lary tangle formation, and damage to synapses and and elucidation of the effects of peripheral processes on
neurons. Several studies have shown that other condi- AD development could lead to improved understand-
tions involving chronic systemic inflammation, such as ing of its pathogenesis. The crucial questions to answer
rheumatoid arthritis and periodontitis, are associated would be precisely how the brain and periphery interact
with an increased risk of AD132,133. These conditions are with each other to affect AD progression, and whether
also associated with elevated levels of Creactive pro- interventions that target systemic factors can modulate
tein and proinflammatory cytokines, such as tumour the pathogenesis or development ofAD.
necrosis factor, IL6 and IL1. These proinflammatory
molecules could participate in AD pathogenesis either Diagnosis
directly, by affecting brain A metabolism (via entry to Several PET radiotracers can be used to detect A in the
the CNS through the BBB or neural afferent pathways brain, and a few biomarkers for AD have been validated
such as the vagus nerve)134,135 or indirectly, by affect- for diagnostic use, including CSF levels of A42, total tau
ing A metabolism in the periphery. In this regard, the and phosphorylated tau. However, these approaches are
results of observational studies show that NSAID use is either invasive or expensive, and are impractical for the
Approaches to improve peripheral A clearance via treatment should have a corresponding focus not only on
enhancing phagocytosis45, proteolytic degradation and pathological changes in the brain but also on peripheral
excretion155,156, and identification of rejuvenation factors abnormalities, which vary among individuals. Identifying
in blood68, are other promising systemic therapeutic these peripheral abnormalities might offer new oppor-
strategies forAD157. tunities for diagnosis of early AD and lead to the design
of specific treatment strategies for individuals with pre-
Conclusions clinical, prodromal or frank AD. In conclusion, the sys-
AD might be not only a brain disorder, but also a systemic temic view of AD proposed in this Review provides a
disease with widespread abnormalities beyond the brain. novel perspective for understanding the pathogenesis of
Thus, systemic factors might interact with brain-related this disease, and fosters new opportunities for its early
factors to modify the AD process. AD diagnosis and diagnosis and successful management.
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