Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease

Farfara, Dorit; Lifshitz, Veronica; Frenkel, Dan

doi:10.1111/j.1582-4934.2008.00314.x

Cited by 191 publications

(146 citation statements)

References 198 publications

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“…Although most research has focused on the effect of Tau protein tangles and A␤ plaques on neuronal function and survival, it is now well established that astrocytes also play a role in AD pathology (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In the CNS, astrocytes are indispensable for the support of neurons.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

Wang¹,

Dinkins²,

He³

et al. 2012

Journal of Biological Chemistry

327

305

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Background:In AD, amyloid protein is associated with neurodegeneration, which may involve amyloid effects on astrocytes. Results: In astrocytes, amyloid peptide triggers secretion of proapoptotic exosomes ("apoxosomes") that are associated with ceramide and PAR-4. Conclusion: Activation of nSMase2 and expression of PAR-4 is critical for the secretion of apoxosomes and glial apoptosis. Significance: Apoxosomes may contribute to glial apoptosis, and therefore, neurodegeneration in AD.Amyloid protein is well known to induce neuronal cell death, whereas only little is known about its effect on astrocytes. We found that amyloid peptides activated caspase 3 and induced apoptosis in primary cultured astrocytes, which was prevented by caspase 3 inhibition. Apoptosis was also prevented by shRNA-mediated down-regulation of PAR-4, a protein sensitizing cells to the sphingolipid ceramide. Consistent with a potentially proapoptotic effect of PAR-4 and ceramide, astrocytes surrounding amyloid plaques in brain sections of the 5xFAD mouse (and Alzheimer disease patient brain) showed caspase 3 activation and were apoptotic when co-expressing PAR-4 and ceramide. Apoptosis was not observed in astrocytes with deficient neutral sphingomyelinase 2 (nSMase2), indicating that ceramide generated by nSMase2 is critical for amyloid-induced apoptosis. Antibodies against PAR-4 and ceramide prevented amyloid-induced apoptosis in vitro and in vivo, suggesting that apoptosis was mediated by exogenous PAR-4 and ceramide, potentially associated with secreted lipid vesicles. This was confirmed by the analysis of lipid vesicles from conditioned medium showing that amyloid peptide induced the secretion of PAR-4 and C18 ceramide-enriched exosomes. Exosomes were not secreted by nSMase2-deficient astrocytes, indicating that ceramide generated by nSMase2 is critical for exosome secretion. Consistent with the ceramide composition in amyloid-induced exosomes, exogenously added C18 ceramide restored PAR-4-containing exosome secretion in nSMase2-deficient astrocytes. Moreover, isolated PAR-4/ceramide-enriched exosomes were taken up by astrocytes and induced apoptosis in the absence of amyloid peptide. Taken together, we report a novel mechanism of apoptosis induction by PAR-4/ceramide-enriched exosomes, which may critically contribute to Alzheimer disease.

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Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

Wang¹,

Dinkins²,

He³

et al. 2012

Journal of Biological Chemistry

327

305

View full text Add to dashboard Cite

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“…Neuronal excitotoxicity leading to neuronal death [34,35] Hyperphosphorylated tau Formation of neurofibrillary tangles [36,37] Inflammation Exacerbation of tau pathology [38] , induction of Aβ release from neurons [39] , attenuation of long-term potentiation [40] , retraction of synapses [41] Metal ion dyshomeostasis Promotion of Aβ aggregation [42,43] Mutations in genes for presenillin-1 and -2, and Increased Aβ levels, linked to Aβ accumulation [44][45][46] amyloid precursor protein; ApoE 4 allele genotype Neurosci Bull February 1, 2013, 29(1): 111-120 114 thologies leads to increased Aβ production [67] . This finding may well explain the sporadic AD which does not involve mutations of genes implicated in Aβ generation.…”

Section: Glutamate Increasesmentioning

confidence: 99%

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

et al. 2012

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There is no effective drug to treat Alzheimer's disease (AD), a neurodegenerative disease affecting an estimated 30 million people around the world. Strongly supported by preclinical and clinical studies, amyloid-beta (Aβ) may be a target for developing drugs against AD. Meanwhile, the fact that localized neuronal death/loss and synaptic impairment occur in AD should also be considered. Neuronal regeneration, which does not occur normally in the mammalian central nervous system, can be promoted by neurotrophic factors (NTFs). Evidence from clinical trials has shown that both Aβ clearance and NTFs are potentially effective in treating AD, thus a new approach combining Aβ clearance and administration of NTFs may be an effective therapeutic strategy.Keywords: Alzheimer's disease; amyloid-beta; neurotrophic factors; treatment IntroductionAlzheimer's disease (AD) is an age-related, progressive and irreversible neurodegenerative disease that causes serious cognitive dysfunction. Its pathological hallmarks are extracellular deposits of amyloid-beta (Aβ) and intracellular neurofibrillary tangles, together with drastic synaptic and neuronal reduction or loss [1] . It has been estimated that AD affects 30 million people around the world [2] , and the past two decades have witnessed an explosion in research into the underlying mechanisms as well as potential therapeutic strategies. Although it was first described by German psychiatrist Alois Alzheimer in 1906, there is still no cure for AD, partly because the cellular and molecular mechanisms underlying it are far from clear. The Food and Drug Administration in the United Stateshas approved a limited range of drugs to treat AD, including acetylcholinesterase inhibitors (AChEIs) and N-methyl-Daspartate receptor (NMDAR) antagonists [3] , although their effects are merely symptomatic and memory-improvement occurs within a limited period. Donepezil, galantamine, rivastigmine and tacrine are AChEIs that prevent the breakdown of acetylcholine released from presynaptic terminals, increasing the residence time of the neurotransmitter within the synapse and thereby prolonging the duration of its interaction with postsynaptic receptors [4] . Memantine, an NMDAR antagonist, has been approved for the treatment of moderate and severe AD; it works by preventing the excitatory neurotoxicity induced by excessive glutamate [5] .Currently, no available pharmacological agents cure or reverse the progression of this devastating neurological disorder. It is therefore urgent to improve our understanding of its pathogenesis, and then develop an effective treatment strategy. This review aimed to provide insights Neurosci Bull February 1, 2013, 29(1): 111-120 112 into the design of potentially effective pharmaceutical treatments for AD by targeting two seemingly separate but tightly connected components, Aβ and neurotrophic factors (NTFs). Aβ as a Promising Target for AD TreatmentAβ is a peptide of 36-43 amino-acids produced from amyloid precursor protein (APP) through aberrant cleavage by...

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“…In the central nervous system (CNS), glial cells have supportive roles for neurons but also act as the resident immune system cells, engaging several inflammatory processes to defend the brain from pathogens and helping it to recover from stress and injury (Farfara et al, 2008). However, in brain pathologies, chronic glial activation is a common event, which could promote a progressive dysfunction and loss of neurons in the CNS.…”

Section: Introductionmentioning

confidence: 99%

An efficient method to limit microglia-dependent effects in astroglial cultures

Losciuto

Dorban

Gabel

et al. 2012

Journal of Neuroscience Methods

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Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease

Cited by 191 publications

References 198 publications

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

An efficient method to limit microglia-dependent effects in astroglial cultures

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