Astrocytes in Alzheimer's Disease

Verkhratsky, Alexei; Olabarria, Markel; Noristani, Harun N.; Yeh, Chia-Yu; Rodrı́guez, José J.

doi:10.1016/j.nurt.2010.05.017

Cited by 384 publications

(334 citation statements)

References 207 publications

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“…Recently, we reported the concomitant occurrence of astroglial atrophy and astrogliosis in the HC of the transgenic mice model of AD. The atrophy appears as a generalized process, whereas astrogliosis was triggered by developing SPs and Ab aggregates (Rodríguez et al, 2009b;Heneka et al, 2010;Olabarria et al, 2010;Verkhratsky et al, 2010;Rodríguez and Verkhratsky, 2011). In the present paper, we extended our analysis of AD-associated changes in astroglia to the EC.…”

Section: Introductionmentioning

confidence: 69%

“…Nevertheless, it should be noted that there is no recovery of atrophic astrocytes in transgenic mice in the superficial layers at later ages but a decrease in GFAP in non-Tg controls, implying an aging effect on control animals ( Figure 3). Astroglia sustain multiple functions, including balance of neurotransmitters, release of trophic factors, metabolic support and extracellular ion buffering, all of which maintain brain physiology and support neuronal connectivity (Danbolt, 2001;Nedergaard et al, 2003;Wang and Bordey, 2008;Verkhratsky et al, 2010Verkhratsky et al, , 2011. In addition, astrocytes are able to sense synaptic activity, regulate synaptic plasticity and synchronize neuronal networks, thus being involved in conscience and cognitive processes (Araque et al, 1999;Fellin et al, 2004;Henneberger et al, 2010;Lalo et al, 2006Lalo et al, , 2011.…”

Section: Discussionmentioning

confidence: 99%

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P1‐178: Early astrocytic atrophy in the Entorhinal cortex of a triple transgenic animal model of Alzheimer's disease

Yeh

Olabarria

Noristani

et al. 2010

Alzheimer's & Dementia

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The EC (entorhinal cortex) is fundamental for cognitive and mnesic functions. Thus damage to this area appears as a key element in the progression of AD (Alzheimer's disease), resulting in memory deficits arising from neuronal and synaptic alterations as well as glial malfunction. In this paper, we have performed an in-depth analysis of astroglial morphology in the EC by measuring the surface and volume of the GFAP (glial fibrillary acidic protein) profiles in a triple transgenic mouse model of AD [3xTg-AD (triple transgenic mice of AD)]. We found significant reduction in both the surface and volume of GFAP-labelled profiles in 3xTg-AD animals from very early ages (1 month) when compared with non-Tg (non-transgenic) controls (48 and 54%, reduction respectively), which was sustained for up to 12 months (33 and 45% reduction respectively). The appearance of Ab (amyloid b-peptide) depositions at 12 months of age did not trigger astroglial hypertrophy; nor did it result in the close association of astrocytes with senile plaques. Our results suggest that the AD progressive cognitive deterioration can be associated with an early reduction of astrocytic arborization and shrinkage of the astroglial domain, which may affect synaptic connectivity within the EC and between the EC and other brain regions. In addition, the EC seems to be particularly vulnerable to AD pathology because of the absence of evident astrogliosis in response to Ab accumulation. Thus we can consider that targeting astroglial atrophy may represent a therapeutic strategy which might slow down the progression of AD.

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Section: Introductionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

P1‐178: Early astrocytic atrophy in the Entorhinal cortex of a triple transgenic animal model of Alzheimer's disease

Yeh

Olabarria

Noristani

et al. 2010

Alzheimer's & Dementia

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“…Packing of the lentivirus using 293T cells and transduction of astrocytes with the virus followed a standard protocol. The shRNA clone (3)(4)(5) with the forward sequence 5Ј-ctagcctgtgattcactgcgttgtttcaagagaacaacgcagtgaatcacaggcttt-3Јand the reverse sequence 5Ј-tcgaaagcctgtgattcactgcgttgttctctggaaacaacgcagtgaatca-3Ј showed successful knockdown of PAR-4 in astrocytes as determined by immunoblotting.…”

Section: Methodsmentioning

confidence: 99%

“…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

318

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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“…In neurodegeneration models, early stages are often associated with atrophy of astroglia, whereas later, astrocytosis and astrocyte activation contribute to the neuroinflammatory component of neurodegeneration. 42,43 Noteworthy, it was shown that proNGF produced by reactive astrocytes in response to oxidative stress promotes motoneuron death in a p75…”

mentioning

confidence: 99%

ProNGF\NGF imbalance triggers learning and memory deficits, neurodegeneration and spontaneous epileptic-like discharges in transgenic mice

et al. 2013

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ProNGF, the precursor of mature nerve growth factor (NGF), is the most abundant form of NGF in the brain. ProNGF and mature NGF differ significantly in their receptor interaction properties and in their bioactivity. ProNGF increases markedly in the cortex of Alzheimer's disease (AD) brains and proNGF\NGF imbalance has been postulated to play a role in neurodegeneration. However, a direct proof for a causal link between increased proNGF and AD neurodegeneration is lacking. In order to evaluate the consequences of increased levels of proNGF in the postnatal brain, transgenic mice expressing a furin cleavage-resistant form of proNGF, under the control of the neuron-specific mouse Thy1.2 promoter, were derived and characterized. Different transgenic lines displayed a phenotypic gradient of neurodegenerative severity features. We focused the analysis on the two lines TgproNGF#3 and TgproNGF#72, which shared learning and memory impairments in behavioral tests, cholinergic deficit and increased Ab-peptide immunoreactivity. In addition, TgproNGF#3 mice developed Ab oligomer immunoreactivity, as well as late diffuse astrocytosis. Both TgproNGF lines also display electrophysiological alterations related to spontaneous epileptic-like events. The results provide direct evidence that alterations in the proNGF/NGF balance in the adult brain can be an upstream driver of neurodegeneration, contributing to a circular loop linking alterations of proNGF/NGF equilibrium to excitatory/inhibitory synaptic imbalance and amyloid precursor protein (APP) dysmetabolism.

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Astrocytes in Alzheimer's Disease

Cited by 384 publications

References 207 publications

P1‐178: Early astrocytic atrophy in the Entorhinal cortex of a triple transgenic animal model of Alzheimer's disease

P1‐178: Early astrocytic atrophy in the Entorhinal cortex of a triple transgenic animal model of Alzheimer's disease

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

ProNGF\NGF imbalance triggers learning and memory deficits, neurodegeneration and spontaneous epileptic-like discharges in transgenic mice

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