Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: Findings from the Nun Study

Riley, Kathryn; Snowdon, David A.; Markesbery, William R.

doi:10.1002/ana.10161

Cited by 357 publications

(266 citation statements)

References 58 publications

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“…Furthermore, the spatiotemporal development of NFT in AD is correlated to the clinical severity of the disease and the cognitive decline of the patients [136]. Initial NFT formation is found in the transentorhinal region in the temporal lobe.…”

Section: Accumulation Of Ndna Damage or Neuron Loss: Implications Formentioning

confidence: 99%

Accumulation of nuclear DNA damage or neuron loss: Molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases

et al. 2008

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According to a long-standing hypothesis, aging is mainly caused by accumulation of nuclear (n) DNA damage in differentiated cells such as neurons due to insufficient nDNA repair during lifetime. In line with this hypothesis it was until recently widely accepted that neuron loss is a general consequence of normal aging, explaining some degree of decline in brain function during aging. However, with the advent of more accurate procedures for counting neurons, it is currently widely accepted that there is widespread preservation of neuron numbers in the aging brain, and the changes that do occur are relatively specific to certain brain regions and types of neurons. Whether accumulation of nDNA damage and decline in nDNA repair is a general phenomenon in the aging brain or also shows cell-type specificity is, however, not known. It has not been possible to address this issue with the biochemical and molecular-biological methods available to study nDNA damage and nDNA repair. Rather, it was the introduction of autoradiographic methods to study quantitatively the relative amounts of nDNA damage (measured as nDNA single-strand breaks) and nDNA repair (measured as unscheduled DNA synthesis) on tissue sections that made it possible to address this question in a cell-type-specific manner under physiological conditions. The results of these studies revealed a formerly unknown inverse relationship between age-related accumulation of nDNA damage and age-related impairment in nDNA repair on the one hand, and the age-related, selective, loss of neurons on the other hand. This inverse relation may not only reflect a fundamental process of aging in the central nervous system but also provide the molecular basis for a new approach to understand the selective neuronal vulnerability in neurodegenerative diseases, particularly Alzheimer's disease.

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Section: Accumulation Of Ndna Damage or Neuron Loss: Implications Formentioning

confidence: 99%

Accumulation of nuclear DNA damage or neuron loss: Molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases

et al. 2008

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“…Recent functional evidence suggests that Aβ initiates the AD changes, but pathological tau protein causes neurodegeneration and better correlates with the clinical manifestation of the disease (Arriagada et al ., 1992; Riley et al ., 2002). While we know that NFTs are mainly composed of abnormally hyperphosphorylated tau that aggregates into paired helical filaments and straight filaments, the mechanisms leading to the abnormal hyperphosphorylation of tau in the brain of AD patients remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase

Lauretti

Praticò

2015

Aging Cell

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SummaryAlterations of glucose metabolism have been observed in Alzheimer's disease (AD) brain. Previous studies showed that glucose deprivation increases amyloidogenesis via a BACE‐1‐dependent mechanism. However, no data are available on the effect that this condition may have on tau phosphorylation. In this study, we exposed neuronal cells to a glucose‐free medium and investigated the effect on tau phosphorylation. Compared with controls, cells incubated in the absence of glucose had a significant increase in tau phosphorylation at epitopes Ser202/Thr205 and Ser404, which was associated with a selective activation of the P38 mitogen‐activated protein kinase. Pharmacological inhibition of this kinase prevented the increase in tau phosphorylation, while fluorescence studies revealed its co‐localization with phosphorylated tau. The activation of P38 was secondary to the action of the apoptosis signal‐regulating kinase 1, as its down‐regulation prevented it. Finally, glucose deprivation induced cell apoptosis, which was associated with a significant increase in both caspase 3 and caspase 12 active forms. Taken together, our studies reveal a new mechanism whereby glucose deprivation can modulate AD pathogenesis by influencing tau phosphorylation and suggest that this pathway may be a new therapeutic target for AD.

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“…In a triple transgenic mouse model, intraneuronal accumulation of Aβ was shown to be associated with deficits in synaptic plasticity before AD lesions developed. [33] Conversely, other autopsy studies [11,26,38] reported NFT to be the dominant lesion in AD and mild cognitive impairment.…”

Section: Discussionmentioning

confidence: 96%

Characterization of Japanese-American men with a single neocortical AD lesion type

Petrovitch

Ross

et al. 2008

Neurobiology of Aging

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Neocortical neuritic plaques (NP) and neurofibrillary tangles (NFT) are hallmarks of Alzheimer's disease (AD) and usually, both are present. The Honolulu-Asia Aging Study autopsy series includes a significant number of individuals with only one neocortical AD lesion type. These could represent an early phase of the AD process. If so, such individuals would be expected to share other clinical and pathological features of AD. We compared frequency of apolipoprotein epsilon E4 (APOE4) allele, average Braak stage, and burden of cerebral amyloid angiopathy (CAA) among the two single lesion type groups, a group without AD lesions, and groups with high and low frequencies of both AD lesions. Single AD lesion groups shared only the characteristics associated with their unique lesion type with the combined AD lesion group and did not have higher prevalence of dementia than the no AD lesion group. Only the NP+NFT group showed a "dose response" relationship with greater probability of dementia with higher neocortical frequencies of either AD lesion. The single neocortical AD lesion groups do not appear to represent early AD.

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Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: Findings from the Nun Study

Cited by 357 publications

References 58 publications

Accumulation of nuclear DNA damage or neuron loss: Molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases

Accumulation of nuclear DNA damage or neuron loss: Molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases

Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase

Characterization of Japanese-American men with a single neocortical AD lesion type

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