Evidence for lymphatic Aβ clearance in Alzheimer's transgenic mice

Pappolla, Miguel A.; Sambamurti, Kumar; Vidal, Rubén; Pacheco‐Quinto, Javier; Pöeggeler, Burkhard; Matsubara, Etsuro

doi:10.1016/j.nbd.2014.07.012

Cited by 50 publications

(48 citation statements)

References 33 publications

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“…2). Consistently, recent reports indicate that Aβ is present in lymph nodes and accumulates with brain amyloid deposition [128]. Lymphatic clearance of Aβ appears to be an overlooked, nevertheless important pathway for Aβ removal, particular in view of the recent GWA studies highlighting the role of several genes involved in trafficking between the brain and lymph nodes.…”

Section: Other Pathways For Aβ Turnovermentioning

confidence: 53%

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

Baranello¹,

Bharani²,

Padmaraju³

et al. 2015

CAR

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260

196

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Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer’s disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin-2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβ turnover.

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Section: Other Pathways For Aβ Turnovermentioning

confidence: 53%

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

Baranello¹,

Bharani²,

Padmaraju³

et al. 2015

CAR

Self Cite

260

196

View full text Add to dashboard Cite

show abstract

“…In EOAD, by contrast, overproduction of Aβ might result in increased absorption of Aβ by the lymphatic system, as demonstrated in a transgenic mouse model of AD, in which increasing Aβ levels in cervical and axillary lymph nodes mirrored increased Aβ levels in the brain. 198 …”

Section: Clearance Of Amyloid-βmentioning

confidence: 99%

Clearance systems in the brain—implications for Alzheimer disease

et al. 2015

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Accumulation of toxic protein aggregates—amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles—is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood–brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.

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“…Drainage of brain antigens has been observed in animal models not only of autoimmune diseases but also of Alzheimer's disease. Aβ, for example, was detected in the cervical lymph nodes in murine models of Alzheimer's disease (85).…”

Section: R E V I E W S E R I E S : G L I a A N D N E U R O D E G E N mentioning

confidence: 99%

Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

Louveau

Plog

Antila

et al. 2017

Journal of Clinical Investigation

481

394

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Evidence for lymphatic Aβ clearance in Alzheimer's transgenic mice

Cited by 50 publications

References 33 publications

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

Clearance systems in the brain—implications for Alzheimer disease

Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

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