Neocortical Neurofibrillary Tangles Correlate With Dementia Severity in Alzheimer's Disease

Bierer, Linda M.; Hof, Patrick R.; Purohit, Dushyant P.; Carlin, Linda; Schmeidler, James; Davis, Kenneth L.; Perl, Daniel P.

doi:10.1001/archneur.1995.00540250089017

Cited by 458 publications

(267 citation statements)

References 39 publications

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“…In contrast to amyloid-β deposition that does not allow the formulation of a coherent distribution scheme (Braak and Braak, 1991) nor a correlation to the cognitive state of the affected individuals (Bierer et al, 1995, Nelson et al, 2012, NFT formation shows a distinct propagation pattern with the disease progression Braak, 1991, Price andMorris, 1999) and correlates well with the cognitive deterioration (Bierer et al, 1995, Nelson et al, 2012. As highlighted by Braak and Braak, the olfactory and limbic pathways of the allocortex are among the first affected brain areas in AD (Fig.…”

Section: Olfactory-limbic Pathways and Admentioning

confidence: 97%

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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Section: Olfactory-limbic Pathways and Admentioning

confidence: 97%

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

et al. 2013

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“…Importantly, as cognitive impairments closely correlate with the extension of tau pathology [132,133], removing neurofibrillary tangles has become one of the main therapeutic goals for the treatment of AD and FTD [134,135]. In this regard, it has been shown that both active and passive immunization against tau reduce its accumulation and slow or prevent behavioral deficits in transgenic mouse models of tauopathy [135][136][137][138][139][140][141][142].…”

Section: Immunotherapy Targeting Taumentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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“…Molecular genetic analyses of subjects with early-onset inherited familial AD (FAD) identified mutations in APP, and presenilins 1 and 2 as the causes of some cases of FAD; in each case the mutation increases the production of the long form of Aβ (Aβ1−42) (De Strooper, 2003;Hardy, 2004). Aβ and tau pathologies are closely associated in ways that suggest a role for Aβ in the formation of neurofibrillary tangles (Giasson et al, 2003), although the number of neurofibrillary tangles is more highly correlated with the severity of cognitive impairment among AD patients than is Aβ pathology (Bierer et al, 1995). Moreover, neurofibrillary tangles are sufficient, in the absence of Aβ pathology, to cause dementia as occurs in patients with fronto-temporal lobe dementia with Parkinsonism linked to chromosome 17 (FTDP-17) caused by tau mutations (Ingram and Spillantini, 2002).…”

Section: Introductionmentioning

confidence: 99%

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

Nelson

Guo

Halagappa

et al. 2007

Experimental Neurology

163

133

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A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five month-old male and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7 month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (Aβ) and numbers of Aβ immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model, suggests that such drugs administered prophylactically might retard the development of AD in humans.

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Neocortical Neurofibrillary Tangles Correlate With Dementia Severity in Alzheimer's Disease

Cited by 458 publications

References 39 publications

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

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

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

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