Clearance systems in the brain—implications for Alzheimer disease

Tarasoff-Conway, Jenna M.; Carare, Roxana O.; Osorio, Ricardo S.; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zloković, Berislav V.; Frangione, Blas; Blennow, Kaj; Ménard, J; Zetterberg, Henrik; Wısnıewskı, Thomas; Leon, Mony J. de

doi:10.1038/nrneurol.2015.119

Cited by 1,166 publications

(1,032 citation statements)

References 211 publications

Supporting

Mentioning

1,007

Contrasting

Unclassified

Order By: Relevance

“…Understanding how Aβ is physiologically cleared from the brain is, therefore, essential. Several potential pathways could clear Aβ from the brain: phagocytosis, endocytosis and macropinocytosis by various cells (such as microglia, perivascular macrophages, astrocytes, oligo dendroglia and neurons); proteolytic degradation by various enzymes (including neprilysin, insulin-degrading enzyme (IDE) and matrix metalloproteinases); and efflux of Aβ to the peripheral circulation, via transportation across the blood-brain barrier (BBB) and blood-CSF barrier, interstitial fluid bulk flow and CSF egress pathways, including arachnoid villi and glymphatic-lymphatic pathways 18 (FIG. 1).…”

Section: Central and Peripheral Clearance Of Aβmentioning

confidence: 99%

“…the brain and the CNS lymphatic vessels (discovered in 2015) 31,32 , might also transport Aβ from the brain to the periphery for clearance 18,33 . However, the glymphaticlymphatic pathway and arachnoid villi are unidirectional; they only mediate Aβ efflux from the CNS to the periphery 18 . Whether peripherally generated Aβ can enter the brain and exert neurotoxic effects there remains poorly understood.…”

Section: Key Pointsmentioning

confidence: 99%

See 1 more Smart Citation

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

View full text Add to dashboard Cite

The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

show abstract

Section: Central and Peripheral Clearance Of Aβmentioning

confidence: 99%

Section: Key Pointsmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

View full text Add to dashboard Cite

show abstract

“…*P < 0.05 vs. WT mice β-secretase and γ-secretase, but it is most precluded by α-secretase to generate neuroprotective and soluble APPα fragments (sAPPα) (MorishimaKawashima 2014). Neprilysin (NEP) and insulindegrading enzyme (IDE) are responsible for proteolytic degradation of Aβ peptides from brain parenchyma (Tanzi et al 2004;Tarasoff-Conway et al 2015). Therefore, we determined whether different Aβ burden between the gray matter and white matter was associated with different expression patterns of these Aβ metabolism-related enzymes.…”

Section: Resultsmentioning

confidence: 99%

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

View full text Add to dashboard Cite

Transgenic APPSwe/PS1dE9 (APP/PS1) mice that overproduce amyloid beta (Aβ) are extensively used in the studies of pathogenesis and experimental therapeutics and new drug screening for Alzheimer's disease (AD). However, most of the current literature uses young or adult APP/PS1 mice. In order to provide a broader view of AD-like phenotype of this animal model, in this study, we systematically analyzed behavioral and pathological profiles of 24-month-old male APP/ PS1 mice. Aged APP/PS1 mice had reference memory deficits as well as anxiety, hyperactivity, and social interaction impairment. Consistently, there was obvious deposition of amyloid plaques in the dorsal hippocampus with decreased expression of insulin-degrading enzyme, a proteolytic enzyme responsible for degradation of intracellular Aβ. Furthermore, decreases in hippocampal volume, neuronal number and synaptophysin expression, and astrocyte atrophy were also observed in aged APP/PS1 mice. This finding suggests that aged APP/PS1 mice can well replicate cognitive and noncognitive behavioral abnormalities, hippocampal atrophy, and neuronal and astrocyte degeneration in AD patients, to enable more objective and refined preclinical evaluation of therapeutic drugs and strategies for AD treatment.

show abstract

“…Most interestingly, we find that deletion of these peripheral immune populations leads to a greater than twofold increase in amyloid burden. Similar to sporadic AD patients, our data reveal that the increase in pathology is not driven by altered Aβ production, but likely via impaired clearance (23)(24)(25). To better understand precisely how Aβ clearance is decreased in Rag-5xfAD mice, we used unbiased GO analysis, which implicated microglia function and changes in both adaptive and innate immunity.…”

Section: Discussionmentioning

confidence: 99%

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Marsh

Abud

Lakatos

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

318

257

View full text Add to dashboard Cite

The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptiveinnate immunity cross talk and accelerated disease progression.is the leading cause of age-related neurodegeneration, affecting over 5.2 million people in the United States alone (1). Pathologically, AD is characterized by two hallmark protein aggregates, amyloid-β (Aβ) plaques and neurofibrillary tangles, that are accompanied by neuroinflammation, including microgliosis, elevated cytokine production, and activation of complement pathways (2-5). Initially, microglia respond to and surround plaques, degrading Aβ by phagocytosis (for review, see refs. 6-8). However, chronic activation of these cells shift microglia to a more proinflammatory and less phagocytic state (9, 10). Although much of the data implicating microglia in AD has come from neuropathological investigation, recent genome-wide association studies have provided the first genetic evidence (to our knowledge) linking microglia dysfunction to AD, with the discovery of risk polymorphisms in several immune system genes: CR1, TREM2, CD33, HLA-DRB5, MS4A6A, and ABCA7 (8,(11)(12)(13)(14)(15).In contrast to the field's increasing understanding of the role of innate immunity in AD, comparatively little is known about whether the adaptive immune system might also influence AD. Those studies that have examined these peripheral populations have largely focused on questions about their potential as biomarkers or their role in active Aβ immunization (3, 16). However, the adaptive and innate immune systems rarely fu...

show abstract

Clearance systems in the brain—implications for Alzheimer disease

Cited by 1,166 publications

References 211 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Contact Info

Product

Resources

About