Alzheimer's Disease and Non-Demented High Pathology Control Nonagenarians: Comparing and Contrasting the Biochemistry of Cognitively Successful Aging

Maarouf, Chera L.; Daugs, Ian D.; Kokjohn, Tyler A.; Walker, Douglas G.; Hunter, Jesse M.; Kruchowsky, Jane; Woltjer, Randy; Kaye, Jeffrey; Castaño, Eduardo M.; Sabbagh, Marwan N.; Beach, Thomas G.

doi:10.1371/journal.pone.0027291

Cited by 68 publications

(89 citation statements)

References 121 publications

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“…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. 49 Of further interest, Aβ 1-42 levels in the brains of high-pathology controls were much higher than those in the brains of aged-matched patients with AD, 50 in agreement with a controversial proposal that Aβ 1-42 may be protective rather than toxic, 51 as further discussed below. In addition, PET imaging studies revealed that cognitive status in patients with AD is inversely correlated with microglial activation, but not Aβ load.…”

Section: Inflammation-a Key Playersupporting

confidence: 77%

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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Section: Inflammation-a Key Playersupporting

confidence: 77%

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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“…Since the identified SNPs are located mainly in CpG islands within the Reelin promoter (Chen et al, 2002), shown to undergo epigenetic modifications as a part of regulatory mechanism of LTP (Levenson et al, 2008, Sui et al, 2012, it would be of highest relevance to further confirm (Kramer et al, 2011) and to check if these SNPs (Seripa et al, 2008) are correlated with a significant increase or decrease of Reelin levels, respectively. In line with Reelin's role in suppressing NFT formation, it is important to mention that elderly people with high AD pathology but no dementia, the so-called high pathology controls (Kramer et al, 2011, Krstic andKnuesel, 2013) differ from AD patients in the amount of NFT load in the frontal cortex (Maarouf et al, 2011). …”

Section: And Promotesmentioning

confidence: 94%

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

et al. 2013

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Alzheimer's disease (AD) is one of the largest unmet medical concerns of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles, the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiological characteristic of late-onset AD. AbstractAlzheimer`s disease (AD) is one of the largest unmet medical needs of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles (NFTs), the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiology characteristic of late-onset AD.3

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“…It has been demonstrated that Aβ1-40 levels were 20-fold higher in AD brains compared to PA brains, whereas Aβ1-42 levels were only twofold higher [42]. Overall, several studies suggested quantitative and qualitative differences in the amyloid deposits between PA and AD brains [43]. It can be concluded that a wide spectrum of harmful effects of Aβ species, peptides, oligomers or plaques coincides with the disturbed presenilin signalling.…”

Section: Presenilin Substrate App and Production Of Toxic β-Amyloid Pmentioning

confidence: 98%

Presenilins Interactome in Alzheimer’s Disease and Pathological Ageing

Wężyk¹,

Żekanowski²

2017

Senescence - Physiology or Pathology

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Alzheimer's disease (AD) is the most common type of dementia characterized by massive neuronal loss. Pathological hallmarks of the disease are overproduction of β-amyloid (Aβ) and hyperphosphorylation of tau protein accumulated into senile plaques (SPs) and neurofibrillary tangles (NFTs), respectively. SPs with cortical tau pathology are also hallmark of pathological ageing (PA). Recently, an extensive overlap has been shown between Aβ levels and profiles in PA and AD brains, suggesting that PA could be a prodromal AD phase. Presenilins are major components of the γ-secretase complex involved in Aβ production. Furthermore, presenilins interact with players of numerous signalling pathways important in the PA and AD. Integration of various modern research approaches would reinforce the role of presenilins signalling network in brain pathology. These approaches include high-throughput (epi)genetic and transcriptomic analyses, large-scale microscopic imaging studies, immunoaffinity purification or mass spectrometry. Comprehensive integration of these methods is necessary to update the definition of the role of presenilins in AD and PA. Hereby, we summarize the available data on presenilins' functions and interactions. We believe that the systematization of the existing knowledge will stimulate further research and will help reveal the molecular nooks and crannies in Alzheimer's disease and in pathological ageing.

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Alzheimer's Disease and Non-Demented High Pathology Control Nonagenarians: Comparing and Contrasting the Biochemistry of Cognitively Successful Aging

Cited by 68 publications

References 121 publications

Deciphering the mechanism underlying late-onset Alzheimer disease

Deciphering the mechanism underlying late-onset Alzheimer disease

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

Presenilins Interactome in Alzheimer’s Disease and Pathological Ageing

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