Region-specific Dissociation of Neuronal Loss and Neurofibrillary Pathology in a Mouse Model of Tauopathy

Spires, Tara L.; Orne, Jennifer D.; SantaCruz, Karen S.; Pitstick, Rose; Carlson, George A.; Ashe, Karen H.; Hyman, Bradley T.

doi:10.2353/ajpath.2006.050840

Cited by 361 publications

(368 citation statements)

References 45 publications

(51 reference statements)

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“…Phosphorylated tau stabilizes the internal structure of healthy neurons, but in AD, tau proteins are hyperphosphorylated and tangle together. Again, recent evidence points to soluble tau rather than NFT as a cause of neuronal loss in AD [18][19][20]. When researchers turned off the mutant tau gene in a mouse model of AD, neurodegeneration was halted and cognitive performance improved even though NFT continued to accumulate [19].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Ocular Biomarkers for Early Detection of Alzheimer's Disease

Frost

Martins

Kanagasingam

2010

JAD

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Alzheimer's disease (AD) is the most common form of dementia and is characterized clinically by a progressive decline in memory, learning and executive function and neuropathologically by the presence of cerebral amyloid deposits. Despite a century of research, there is still no cure or conclusive pre-mortem diagnosis for the disease. A number of symptom-modifying drugs for AD have been developed, but their efficacy is minimal and short-lived. AD cognitive symptoms arise only after significant, irreversible neural deterioration has occurred, hence there is an urgent need to detect AD early, before the onset of cognitive symptoms. An accurate, early diagnostic test for AD would enable current and future treatments to be more effective, as well as contribute to the development of new treatments.While most AD related pathology occurs in the brain, the disease has also been reported to affect the eye, which is more accessible for imaging than the brain. AD-related proteins exist in the normal human eye and may produce ocular pathology in AD. There is some homology between the retinal and cerebral vasculatures and the retina also contains nerve cells and fibers that form a sensory extension of the brain. The eye is the only place in the body where vasculature or neural tissue is available for non-invasive optical imaging. This article presents a review of current literature on ocular morphology in AD and discusses the potential for an ocular based screening test for AD.

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Section: Alzheimer's Diseasementioning

confidence: 99%

Ocular Biomarkers for Early Detection of Alzheimer's Disease

Frost

Martins

Kanagasingam

2010

JAD

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“…In histologic studies, NFTs are associated with immunohistochemical evidence of caspase activation and caspase-cleavage products, leading to the hypothesis that NFTs cause apoptotic death (Gamblin et al, 2003;Rissman et al, 2004). However, some data from cell culture experiments, mouse models, and disease caused by tau mutations that causes cell death but not tangle formation indicate that protein inclusions may be unnecessary for neuronal death or even protect cells from toxic soluble moieties (Saudou et al, 1998;Reed et al, 2001;Bodner et al, 2006;Spires et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Pearson's correlations and Fisher's r to z ( p values) comparing caspase eight levels and neuron number (Spires et al, 2006) were calculated using StatView (SAS Institute, Cary, NC). To compare transgenic to control levels of caspase eight normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) levels, Mann-Whitney U tests were used (caspase mRNA data were not normally distributed).…”

Section: Surgery and Imagingmentioning

confidence: 99%

“…Conventional histological studies of human Alzheimer's disease (AD) and animal models of tauopathies have shown that certain neuronal populations appear to be vulnerable to both neurofibrillary tangle (NFT) formation and neuronal loss (Terry et al, 1981;Arriagada et al, 1992;Lewis et al, 2000;Zehr et al, 2004;Andorfer et al, 2005;Spires et al, 2006) and that neuronal loss outstrips tangle number by orders of magnitude (Gomez-Isla et al, 1997;Spires et al, 2006). These observations give rise to two possible scenarios: vulnerable neurons develop a tangle which eventually causes the cell to die, then the tangle is cleared; or vulnerable neurons either die or develop a tangle.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In VivoImaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons

Spires‐Jones¹,

Calignon²,

Matsui³

et al. 2008

J. Neurosci.

122

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Accumulation of neurofibrillary tangles (NFTs) in Alzheimer's disease correlates with neuronal loss and cognitive decline, but the precise relationship between NFTs and neuronal death and downstream mechanisms of cell death remain unclear. Caspase cleaved products accumulate in tangles, implying that tangles may contribute to apoptotic neuronal death. To test this hypothesis, we developed methods using multiphoton imaging to detect both neurofibrillary pathology and caspase activation in the living mouse brain. We examined rTg4510 mice, a reversible mouse model of tauopathy that develops tangles and neuronal loss. Only a small percentage of imaged neurons were caspase activity positive, but the vast majority of the cells with active caspases contained NFTs. We next tested the hypothesis that caspase activation led to acute, apoptotic neuronal death. Caspase positive cell bodies did not degenerate over hours of imaging, despite the presence of activated executioner caspases. Suppression of the transgene, which stops ongoing death, did not suppress caspase activity. Finally, histochemical assessments revealed evidence of caspase-cleaved tau, but no TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) positive or apoptotic nuclei. With the novel technique of observing NFTs and caspase activation in the living brain, we demonstrate that aggregated tau in neurons can be associated with caspase activation, but that caspase activation is not sufficient to cause acute neuronal death in this model.

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“…Discussion NFT-bearing neurons are characterized by abnormal accumulation of fibrillar tau aggregates in the cell soma and proximal dendrites compared with the predominantly axonal localization of tau in healthy neurons (24). To isolate the consequences of tau aggregation and mislocalization to soma and dendrites (6), we focused on the primary visual cortex, a brain area in which the major driving input source, the lateral geniculate nucleus, is structurally intact (10,25) (Fig. S7).…”

Section: Significancementioning

confidence: 99%

Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo

Kuchibhotla

Wegmann

Kopeikina

et al. 2013

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

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177

136

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Alzheimer's disease (AD) is pathologically characterized by the deposition of extracellular amyloid-β plaques and intracellular aggregation of tau protein in neurofibrillary tangles (NFTs) (1, 2). Progression of NFT pathology is closely correlated with both increased neurodegeneration and cognitive decline in AD (3) and other tauopathies, such as frontotemporal dementia (4,5). The assumption that mislocalization of tau into the somatodendritic compartment (6) and accumulation of fibrillar aggregates in NFTs mediates neurodegeneration underlies most current therapeutic strategies aimed at preventing NFT formation or disrupting existing NFTs (7,8). Although several disease-associated mutations cause both aggregation of tau and neurodegeneration, whether NFTs per se contribute to neuronal and network dysfunction in vivo is unknown (9). Here we used awake in vivo two-photon calcium imaging to monitor neuronal function in adult rTg4510 mice that overexpress a human mutant form of tau (P301L) and develop cortical NFTs by the age of 7-8 mo (10). Unexpectedly, NFT-bearing neurons in the visual cortex appeared to be completely functionally intact, to be capable of integrating dendritic inputs and effectively encoding orientation and direction selectivity, and to have a stable baseline resting calcium level. These results suggest a reevaluation of the common assumption that insoluble tau aggregates are sufficient to disrupt neuronal function.paired helical filaments | tau pathology | neuronal networks N eurofibrillary tangles (NFTs) containing aggregated tau protein (1) have long been considered key players in the progressive neural dysfunction and neurodegeneration observed in Alzheimer's disease (AD) (2, 3) and other tauopathies (4, 5). It is commonly assumed that NFT-bearing neurons exhibit deficits in synaptic integration and eventually lead to neurodegeneration (11,12). However, the actual functional properties of NFT-bearing neurons in intact neural circuits have not been explored previously (13). We addressed this question directly using awake in vivo two-photon calcium imaging in a mouse model of NFT formation (rTg4510) by applying recently developed imaging approaches allowing for single-neuron-level and population-level assessment of neural activity in awake mice (14). Because two-photon calcium imaging allows for measurement of response properties in many neurons simultaneously, we were able to directly isolate the impact of NFT deposition in a neuronal microcircuit by evaluating population-level network dynamics and, more specifically, by differentiating the function of individual NFT-bearing and neighboring non-NFT-bearing neurons.To assess the functional properties of neurons in the visual cortex, we used a genetically encoded ratiometric calcium indicator, yellow cameleon 3.6 (YC3.6), packaged in an adenoassociated viral vector (15,16). To assess functional responses, we exploited the well-characterized functional architecture of visual cortex whereby neurons in mouse visual cortex modulate their activity d...

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Region-specific Dissociation of Neuronal Loss and Neurofibrillary Pathology in a Mouse Model of Tauopathy

Cited by 361 publications

References 45 publications

Ocular Biomarkers for Early Detection of Alzheimer's Disease

Ocular Biomarkers for Early Detection of Alzheimer's Disease

In VivoImaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons

Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo

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