Peripheral infection and aging interact to impair hippocampal memory consolidation

Barrientos, Ruth M.; Higgins, Emily A.; Biedenkapp, Joseph C.; Sprunger, David; Wright-Hardesty, Karli; Watkins, Linda R.; Rudy, Jerry W.; Maier, Steven F.

doi:10.1016/j.neurobiolaging.2005.03.010

Cited by 289 publications

(308 citation statements)

References 43 publications

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“…It has been reported that peripheral injection of E. coli could produce a marked increase of IL-1 level in the hippocampus [96] . Aged rats treated with E. coli 7 d prior to the training in the water maze did not show deficits in acquisition of learning or in short-term retention probe testing, but did show impairment in long-term retention probe testing [95] . In the same study, injection of E. coli 4 d prior to conditioning could impair long-term, but not shortterm memory in contextual fear conditioning in aged rats [95] .…”

Section: Specific Types and Stages Of Memory Memory Appearsmentioning

confidence: 81%

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Interleukin-1β with learning and memory

Huang

Sheng²

2010

Neurosci. Bull.

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Abstract:Interleukin-1 (IL-1) is one of the first cytokines ever described. It has long been recognized to play an important role in mediating inflammation and orchestrating the physiological and behavioral adjustments that occur during sickness.Recently, accumulating evidence has indicated that IL-1 also adversely affects cognitive function. Nevertheless, there are also some reports showing no effects or even beneficial effects of IL-1 on learning and memory. The relationship between IL-1 and cognitive impairment has not been clearly elucidated. Here we reviewed the evidence of both negative and positive effects of IL-1 on learning and memory, and the key factors that may affect the effects of IL-1 on learning and memory were discussed.

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Section: Specific Types and Stages Of Memory Memory Appearsmentioning

confidence: 81%

“…Moreover, Escherichia coli (E. coli) has been revealed to be capable of impairing contextual fear responses and long-term memory in water maze in old rats (24-month-old), but not in young ones (3-month-old) [95] . Similar results have been obtained in another study [96] .…”

Section: Agementioning

confidence: 99%

Interleukin-1β with learning and memory

Huang

Sheng²

2010

Neurosci. Bull.

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“…These results are noteworthy because IL-6 in the periphery plays a role in the pathogenesis of immunologically mediated fatigue and loss of strength (33,34). Furthermore, the hippocampus is densely populated with microglia, and inflammatory cytokines are well known to inhibit working memory (35) and memory consolidation (36) in hippocampaldependent tasks. Although flavonoids can penetrate the bloodbrain barrier (37), it is unclear whether luteolin entered the brain to directly inhibit IL-6 expression or whether it reduced hippocampal IL-6 indirectly by reducing peripheral responses to LPS.…”

Section: Discussionmentioning

confidence: 92%

Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1

Jang¹,

Kelley

Johnson

2008

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

321

192

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Luteolin, a flavonoid found in high concentrations in celery and green pepper, has been shown to reduce production of proinflammatory mediators in LPS-stimulated macrophages, fibroblasts, and intestinal epithelial cells. Because excessive production of proinflammatory cytokines by activated brain microglia can cause behavioral pathology and neurodegeneration, we sought to determine whether luteolin also regulates microglial cell production of a prototypic inflammatory cytokine, IL-6. Pretreatment of primary murine microlgia and BV-2 microglial cells with luteolin inhibited LPS-stimulated IL-6 production at both the mRNA and protein levels. To determine how luteolin inhibited IL-6 production in microglia, EMSAs were performed to establish the effects of luteolin on LPS-induced binding of transcription factors to the NF-B and activator protein-1 (AP-1) sites on the IL-6 promoter. Whereas luteolin had no effect on the LPS-induced increase in NF-B DNA binding activity, it markedly reduced AP-1 transcription factor binding activity. Consistent with this finding, luteolin did not inhibit LPS-induced degradation of I B-␣ but inhibited JNK phosphorylation. To determine whether luteolin might have similar effects in vivo, mice were provided drinking water supplemented with luteolin for 21 days and then they were injected i.p. with LPS. Luteolin consumption reduced LPS-induced IL-6 in plasma 4 h after injection. Furthermore, luteolin decreased the induction of IL-6 mRNA by LPS in hippocampus but not in the cortex or cerebellum. Taken together, these data suggest luteolin inhibits LPS-induced IL-6 production in the brain by inhibiting the JNK signaling pathway and activation of AP-1 in microglia. Thus, luteolin may be useful for mitigating neuroinflammation.cytokines ͉ flavonoids ͉ MAPK ͉ brain ͉ neuroinflammation

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“…71 Hence, the observation that sickness behaviour at young age is relatively benign, whereas systemic inflammation in the elderly can lead to delirium, 72 could be explained by an ageassociated priming of microglia. 73,74 In rodents, acute systemic infection in aged, but not young, animals leads to hippocampus-dependent cognitive impairments, 75,76 and exaggerated and prolonged upregulation of the proinflammatory cytokine IL-1β. 77,78 Chronic inflammatory conditions during ageing are, therefore, expected to profoundly affect the response of microglia towards damage signals that are released by degenerating neurons.…”

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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Peripheral infection and aging interact to impair hippocampal memory consolidation

Cited by 289 publications

References 43 publications

Interleukin-1β with learning and memory

Interleukin-1β with learning and memory

Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1

Deciphering the mechanism underlying late-onset Alzheimer disease

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