Expression Profiles of Cytokines in the Brains of Alzheimer's Disease (AD) Patients Compared to the Brains of Non-Demented Patients with and without Increasing AD Pathology

Morimoto, Kaori; Horio, Juri; Satoh, Haruhisa; Sue, Lucia I.; Beach, Thomas G.; Arita, Seizaburo; Tooyama, Ikuo; Konishi, Y.

doi:10.3233/jad-2011-101815

Cited by 84 publications

(59 citation statements)

References 58 publications

(89 reference statements)

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“…Cytokine profiles in the brain are altered in AD. A recent study demonstrated that IL-1β, IL-10, IL-13, IL-18, IL-33, TGF-β1, and TNF-α converting enzyme are elevated in AD [37]. In the Tg2576 model, TNF-α, IL-1β, and MCP-1 are increased with age and plaque deposition [38].…”

Section: Discussionmentioning

confidence: 99%

Central and Peripheral Administration of Antisense Oligonucleotide Targeting Amyloid-β Protein Precursor Improves Learning and Memory and Reduces Neuroinflammatory Cytokines in Tg2576 (AβPPswe) Mice

Farr

Erickson

Niehoff

et al. 2014

JAD

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease. The World Health Organization estimates that there are currently 18 million people worldwide living with AD and that number is expected to double by early 2025. Currently, there are no therapies to stop or reverse the symptoms of AD. We have developed an antisense oligonucleotide (OL-1) against the amyloid betaprotein precursor (AβPP) that can decrease AβPP expression and amyloid beta protein (Aβ) production. This antisense rapidly crosses the blood-brain barrier, reverses learning and memory impairments, reduces oxidative stress and restores brain-to-blood efflux of Aβ in SAMP8 mice. In the current study, we examined the effects of this AβPP antisense in the Tg2576 mouse model of AD. The Tg2576 overproduces human Aβ, develops age-related learning and memory deficits, and exhibits oxidative damage in the brain. First, we administered the AβPP antisense centrally into the lateral ventricle 3 times at 2 week intervals. Seventy-two hours after the third injection, we tested learning and memory in T-maze foot shock avoidance. In the second study, we injected the mice with AβPP antisense 3 times at two week intervals via the tail vein. Seventy-two hours later, we tested learning and memory T-maze foot shock avoidance, novel object recognition and elevated plus maze. At the end of behavioral testing, mice were sacrificed and brain tissue was collected for evaluation of AβPP, Aβ, and expression of cytokines and chemokines. AβPP antisense administered centrally improved acquisition and retention of T-maze foot shock avoidance. AβPP antisense administered via tail vein improved learning and memory in both T-maze foot shock avoidance and novel object-place recognition. In the elevated plus maze the mice which received OL-1 AβPP antisense spent less time in the open arms and had fewer entries into the open arms indicating reduced disinhibitation. Biochemical analyses reveal significant reduction of AβPP signal and a reduction of measures of neuroinflammation. The current findings support the therapeutic potential of OL-1 AβPP antisense.

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Section: Discussionmentioning

confidence: 99%

Central and Peripheral Administration of Antisense Oligonucleotide Targeting Amyloid-β Protein Precursor Improves Learning and Memory and Reduces Neuroinflammatory Cytokines in Tg2576 (AβPPswe) Mice

Farr

Erickson

Niehoff

et al. 2014

JAD

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“…For example in areas with dense plaque accumulations C1q mRNA increased from 11 to 80 fold compared to normal AD brain (Yasojima et al 1999). In addition pro-inflammatory cyokines, for example the interleukins and TNF␣, have been shown to have increased expression (Morimoto et al 2011). This may constitute a driving force in stimulating local complement protein production.…”

Section: Are Measurements Of Complement Gene Expression Useful As a Bmentioning

confidence: 97%

Complement activation as a biomarker for Alzheimer's disease

et al. 2012

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“…41,42 Nevertheless, extended treatment of asymptomatic individuals with the anti-inflammatory drug naproxen reduced the incidence of AD, supporting a beneficial effect of anti-inflammatory drugs only when administered in early, asymptomatic phases of the disease. 43 Interestingly, patients with high plaque burden without dementia-so-called high-pathology controls 44,45 show almost no evidence of neuroinflammation [46][47][48] and neuro degeneration. 46 These findings are in accordance with results from several transgenic mouse lines that express human versions of AD-inducing mutated genes, which show no evidence of strong neuroinflammatory responses nor widespread progressive neuronal cell death.…”

Section: Inflammation-a Key Playermentioning

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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Expression Profiles of Cytokines in the Brains of Alzheimer's Disease (AD) Patients Compared to the Brains of Non-Demented Patients with and without Increasing AD Pathology

Cited by 84 publications

References 58 publications

Central and Peripheral Administration of Antisense Oligonucleotide Targeting Amyloid-β Protein Precursor Improves Learning and Memory and Reduces Neuroinflammatory Cytokines in Tg2576 (AβPPswe) Mice

Central and Peripheral Administration of Antisense Oligonucleotide Targeting Amyloid-β Protein Precursor Improves Learning and Memory and Reduces Neuroinflammatory Cytokines in Tg2576 (AβPPswe) Mice

Complement activation as a biomarker for Alzheimer's disease

Deciphering the mechanism underlying late-onset Alzheimer disease

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