The role of microglia in amyloid clearance from the AD brain

Lee, C. Y. Daniel; Landreth, Gary E.

doi:10.1007/s00702-010-0433-4

Cited by 556 publications

(433 citation statements)

References 151 publications

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“…However, it has been well established that glia absorb various materials and clear them from the synaptic cleft and that various forms of A␤ are taken up and cleared by glia (Lee and Landreth, 2010). Thus, the finding of oA␤ in the glia cells was expected.…”

Section: Discussionmentioning

confidence: 99%

Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid

Nath¹,

Agholme²,

Kurudenkandy³

et al. 2012

Journal of Neuroscience

218

222

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Alzheimer's disease (AD) is the major cause of dementia. During the development of AD, neurofibrillary tangles progress in a fixed pattern, starting in the transentorhinal cortex followed by the hippocampus and cortical areas. In contrast, the deposition of ␤-amyloid (A␤) plaques, which are the other histological hallmark of AD, does not follow the same strict spatiotemporal pattern, and it correlates poorly with cognitive decline. Instead, soluble A␤ oligomers have received increasing attention as probable inducers of pathogenesis. In this study, we use microinjections into electrophysiologically defined primary hippocampal rat neurons to demonstrate the direct neuron-to-neuron transfer of soluble oligomeric A␤. Additional studies conducted in a human donor-acceptor cell model show that this A␤ transfer depends on direct cellular connections. As the transferred oligomers accumulate, acceptor cells gradually show beading of tubulin, a sign of neurite damage, and gradual endosomal leakage, a sign of cytotoxicity. These observations support that intracellular A␤ oligomers play a role in neurodegeneration, and they explain the manner in which A␤ can drive disease progression, even if the extracellular plaque load is poorly correlated with the degree of cognitive decline. Understanding this phenomenon sheds light on the pathophysiological mechanism of AD progression. Additional elucidation will help uncover the detailed mechanisms responsible for the manner in which AD progresses via anatomical connections and will facilitate the development of new strategies for stopping the progression of this incapacitating disease.

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Section: Discussionmentioning

confidence: 99%

Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid

Nath¹,

Agholme²,

Kurudenkandy³

et al. 2012

Journal of Neuroscience

218

222

View full text Add to dashboard Cite

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“…Phagocytosis of extracellular aggregates by specialized cells is a documented feature of amyloid diseases. Microglia and astrocytes have been reported as fundamental in the clearance of A␤ plaques both in vivo and in cell culture (64,65). Despite professional phagocytes being responsible for this function in vivo, it must be considered that most of the non-professional phagocytic cell lines are capable of phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

Sequence-dependent Internalization of Aggregating Peptides

Couceiro

Gallardo

Smet

et al. 2015

Journal of Biological Chemistry

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Background: Prionoid propagation requires cell internalization of aggregated polypeptides. Results: Aggregates of different sequence are internalized through different endocytic pathways. Only phagocytosed aggregates (Ͼ1 m) elicit an HSF1-dependent proteostatic response. Conclusion: Proteostatic response upon aggregate internalization differs markedly depending on the sequence. Significance: The characterization of mechanisms of cell penetration is fundamental for the understanding of aggregate transmission in disease.

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“…A broadly accepted view holds that microglia are recruited to clear Aβ aggregates, 79 but ablation of microglia does not influence the formation and maintenance of Aβ deposits in a mouse model of AD. 80 Similarly, after uptake of soluble and fibrillary Aβ by microglia, a large fraction of both species are released without degradation.…”

Section: Aged and Primed Microgliamentioning

confidence: 99%

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-(A) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between A and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of A accumulation in late-onset AD. Abstract | Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence ...

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The role of microglia in amyloid clearance from the AD brain

Cited by 556 publications

References 151 publications

Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid

Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid

Sequence-dependent Internalization of Aggregating Peptides

Deciphering the mechanism underlying late-onset Alzheimer disease

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