Activation of Microglia Acidifies Lysosomes and Leads to Degradation of Alzheimer Amyloid Fibrils

Majumdar, Amitabha; Cruz, Dana; Asamoah, Nikiya; Buxbaum, Adina R.; Sohár, István; Lobel, Peter; Maxfield, Frederick R.

doi:10.1091/mbc.e06-10-0975

Cited by 230 publications

(236 citation statements)

References 42 publications

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“…Interestingly, it was recently reported (based on genetic perturbations) that microglial PGRN limits amyloid plaque deposition in a mouse AD model (31). However, although microglia can phagocytose and digest aggregated Aβ in a lysosome-dependent manner (22,62,63), our data indicate that they contributed only a small part to the steady-state pool of PGRN and lysosomes around amyloid plaques. Our results do not rule out physiologically important roles for microglia and their lysosomes in β-amyloid metabolism, as proposed by recent studies (64)(65)(66).…”

Section: Discussioncontrasting

confidence: 47%

“…Similar structures were described in seminal electron-microscopy studies of human AD brain tissue (9). Given the central role for lysosomes as sites of macromolecule degradation, combined with roles for microglia in amyloid plaque phagocytosis and clearance (22,23), we next investigated the contributions of microglia to these plaque-associated lysosome accumulations.…”

Section: Ultrastructural Analysis Of Organelle Accumulation Surroundingmentioning

confidence: 99%

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Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

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

327

326

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Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.

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Section: Discussioncontrasting

confidence: 47%

Section: Ultrastructural Analysis Of Organelle Accumulation Surroundingmentioning

confidence: 99%

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

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

327

326

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“…The A␤ levels are determined by the balance between its production and degradation/clearance, and an attenuated A␤ catabolism is suggested to cause A␤ accumulation in aging brains (14). Previous studies have shown that astrocytes and microglia directly take up and degrade A␤42 (15,16) and that A␤ degradation occurs in late endosomal-lysosomal compartments (17,18). These lines of evidence, together with the finding that LPL mediates the cellular uptake of lipoproteins (1,2), led us to carry out experiments to determine whether LPL interacts with A␤ to promote A␤ cellular uptake and degradation in astrocytes.…”

mentioning

confidence: 98%

Lipoprotein Lipase Is a Novel Amyloid β (Aβ)-binding Protein That Promotes Glycosaminoglycan-dependent Cellular Uptake of Aβ in Astrocytes

Nishitsuji

Hosono

Uchimura

et al. 2011

Journal of Biological Chemistry

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Lipoprotein lipase (LPL) is a member of a lipase family known to hydrolyze triglyceride molecules in plasma lipoprotein particles. LPL also plays a role in the binding of lipoprotein particles to cell-surface molecules, including sulfated glycosaminoglycans (GAGs). LPL is predominantly expressed in adipose and muscle but is also highly expressed in the brain where its specific roles are unknown. It has been shown that LPL is colocalized with senile plaques in Alzheimer disease (AD) brains, and its mutations are associated with the severity of AD pathophysiological features. In this study, we identified a novel function of LPL; that is, LPL binds to amyloid ␤ protein (A␤) and promotes cell-surface association and uptake of A␤ in mouse primary astrocytes. The internalized A␤ was degraded within 12 h, mainly in a lysosomal pathway. We also found that sulfated GAGs were involved in the LPL-mediated cellular uptake of A␤. Apolipoprotein E was dispensable in the LPL-mediated uptake of A␤. Our findings indicate that LPL is a novel A␤-binding protein promoting cellular uptake and subsequent degradation of A␤. Lipoprotein lipase (LPL)2 catalyzes the hydrolysis of triacylglycerol and mediates the cellular uptake of lipoproteins by functioning as a "bridging molecule" between lipoproteins and sulfated glycosaminoglycans (GAGs) or lipoprotein receptors in blood vessels (1, 2). Sulfated GAGs are side chains of proteoglycans normally found in the extracellular matrix and on the cell surface in the peripheral tissues and brain. Sulfation modifications vary within the GAG chains and are crucial for interaction between GAGs and various protein ligands (3), including LPL (4, 5).It has been shown that LPL is distributed in numerous organs and is highly expressed in the brain (6, 7). Although the catabolic activity of LPL on triacylglycerol is observed in the brain (8), the finding that apolipoprotein CII (apoCII), an essential cofactor for LPL, is not expressed in the brain (9, 10), suggests that LPL has a novel nonenzymatic function in the brain. However, little is known about LPL function in the brain. Interestingly, it has been shown that LPL is accumulated in senile plaques of Alzheimer disease (AD) brains (11). Moreover, SNPs in the coding region of the LPL gene are associated with disease incidence in clinically diagnosed AD subjects, LPL mRNA expression level, brain cholesterol level, and the severity of AD pathologies, including neurofibrillary tangles and senile plaque density (12). These results suggest that LPL may have a physiological role in the brain, whose alternation is associated with the pathogenesis of AD.The occurrence of senile plaques in the brain is one of the pathological hallmarks of AD. They contain extracellular deposits of amyloid ␤ protein (A␤), and the abnormal A␤ deposition or the formation of soluble A␤ oligomers is crucial for AD pathogenesis. A␤ is a physiological peptide whose main species are 40 and 42 amino acids in length, and A␤42 is the predominant specie in senile plaques (13). The A␤ level...

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“…Finally, a new drug potentially useful in the treatment of both diseases is ademetionine, an antidepressant (depression is one of the main psychiatric symptoms of AD) that appears to reduce the aggregation of β-amyloid fibrils [183,184] and shows neuroprotective effects on RGCs [185,186].…”

Section: Glutamate Modulationmentioning

confidence: 99%

Critical Review on the Relationship between Glaucoma and Alzheimer's Disease

Pescosolido¹,

Pascarella²,

Buomprisco³

et al. 2014

AOVS

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two distinct pathologies, despite similar pathophysiology and demographic distribution. Both diseases are neurodegenerative, chronic and progressive in nature, with irreversible neuronal cell loss. Furthermore, both POAG and AD disease primarily affect the elderly, with a strongly age-dependent incidence. The progressive debilitating course of both diseases has tremendous implications on an aging population [1]. For years Glaucoma has been associated with high IOP [2], although scientists had accepted this etiology with caution, since it was known that POAG could develop in subjects with normal or even low IOP. In fact, one out of three POAG patients has normotensive or low tension glaucoma [3]. This observation has led the scientific community to look for other possible causes of this slowly debilitating pathogenesis.The hallmark of neurodegenerative diseases is the death of specific neuron populations, and of those other neurons that are inter-connected and depend for their survival on the inputs from the main population (trans-synaptic degeneration). In Parkinson's disease accumulation of alfa-synuclein [4] causes the degeneration of dopaminergic neurons of the substantia nigra, in the midbrain, thus leading to the classic symptoms of Parkinson's such as tremor, akinesia, bradykinesia, and stiffness [5]. In AD there is a loss of neurons in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus [6]. Both amyloid plaques and neurofibrillary tangles are AbstractA third of people affected by primary open angle glaucoma (POAG) have normal or even low intraocular pressure (IOP), such as in the case of normotensive glaucoma and low pressure glaucoma. Therefore, high IOP, while remaining the most important risk factor for POAG development, is not the only one. POAG has been recognized to belong to the class of neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's, and several recent studies have suggested possible links between Alzheimer's and glaucoma both from an epidemiological and a pathogenetic point of view. In fact, several pathogenetic factors are common between the two diseases: the diffuse axonal degeneration of ganglion cells, the presence of specific markers (such as amyloid-β) in the aqueous humor, the activation of caspases and the abnormal processing of amyloid precursor protein in retinal ganglion cells, the reduction of the intracranial pressure of the cerebrospinal fluid, the mutations of the gene that encodes for optineurine. Conflicting data have been reported concerning apolipoprotein E. Finally, numerous publications affirm the utility of molecules traditionally used in the treatment of neurodegenerative diseases (e.g. forskolin, L-carnosine, homotaurine, folic acid, acetylcholinesterase inhibitors, antioxidant vitamins, glatiramer acetate, etc.) also in the treatment of glaucoma.In the present research we ana...

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Activation of Microglia Acidifies Lysosomes and Leads to Degradation of Alzheimer Amyloid Fibrils

Cited by 230 publications

References 42 publications

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Lipoprotein Lipase Is a Novel Amyloid β (Aβ)-binding Protein That Promotes Glycosaminoglycan-dependent Cellular Uptake of Aβ in Astrocytes

Critical Review on the Relationship between Glaucoma and Alzheimer's Disease

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