Tangle-bearing neurons survive despite disruption of membrane integrity in a mouse model of tauopathy

Neurofibrillary tangles (NFTs) are associated with neuronal loss and correlate with cognitive impairment in Alzheimer disease, but how NFTs relate to neuronal death is not clear. We studied cell death in Tg4510 mice that reversibly express P301L mutant human tau and accumulate NFTs using in vivo multiphoton imaging of neurofibrillary pathology, propidium iodide (PI) incorporation into cells, caspase activation and DNA labeling. We first observed that in live mice a minority of neurons was labeled with the caspase probe or with PI fluorescence. These markers of cell stress were localized in the same cells and appeared to be specifically within NFT-bearing neurons. Contrary to expectations, the PI-stained neurons did not die over a day of observation; the presence of Hoechst-positive nuclei in them on the subsequent day indicated that the NFT-associated membrane disruption suggested by PI staining and caspase activation do not lead to acute death of neurons in this tauopathy model. This unique combination of in vivo multiphoton imaging with markers of cell death and pathologic alteration is a powerful tool for investigating neuronal damage associated with neurofibrillary pathology

T cell mediated cerebral hemorrhages and microhemorrhages during passive Aβ immunization in APPPS1 transgenic mice

<p>Abstract</p> <p>Background</p> <p>Immunization against amyloid-β (Aβ), the peptide that accumulates in the form of senile plaques and in the cerebrovasculature in Alzheimer's disease (AD), causes a dramatic immune response that prevents plaque formation and clears accumulated Aβ in transgenic mice. In a clinical trial of Aβ immunization, some patients developed meningoencephalitis and hemorrhages. Neuropathological investigations of patients who died after the trial showed clearance of amyloid pathology, but also a powerful immune response involving activated T cells probably underlying the negative effects of the immunization.</p> <p>Results</p> <p>To define the impact of T cells on this inflammatory response we used passive immunization and adoptive transfer to separate the effect of IgG and T cell mediated effects on microhemorrhage in APPPS1 transgenic mice. Neither anti Aβ IgG nor adoptively transferred T cells, alone, led to increased cerebrovascular damage. However, the combination of adoptively transferred T cells and passive immunization led to massive cerebrovascular bleeding that ranged from multiple microhemorrhages in the parenchyma to large hematomas.</p> <p>Conclusions</p> <p>Our results indicate that vaccination can lead to Aβ and T cell induced cerebral micro-hemorrhages and acute hematomas, which are greatly exacerbated by T cell mediated activity.</p

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember&#8482;, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe

Monitoring protein aggregation and toxicity in Alzheimer's disease mouse models using in vivo imaging

Aggregation of amyloid beta peptide into senile plaques and hyperphosphorylated tau protein into neurofibrillary tangles in the brain are the pathological hallmarks of Alzheimer’s disease. Despite over a century of research into these lesions, the exact relationship between pathology and neurotoxicity has yet to be fully elucidated. In order to study the formation of plaques and tangles and their effects on the brain, we have applied multiphoton in vivo imaging of transgenic mouse models of Alzheimer’s disease. This technique allows longitudinal imaging of pathological aggregation of proteins and the subsequent changes in surrounding neuropil neurodegeneration and recovery after therapeutic interventions

Hyperphosphorylation and Cleavage at D421 Enhance Tau Secretion

It is well established that tau pathology propagates in a predictable manner in Alzheimer’s disease (AD). Moreover, tau accumulates in the cerebrospinal fluid (CSF) of AD’s patients. The mechanisms underlying the propagation of tau pathology and its accumulation in the CSF remain to be elucidated. Recent studies have reported that human tau was secreted by neurons and non-neuronal cells when it was overexpressed indicating that tau secretion could contribute to the spreading of tau pathology in the brain and could lead to its accumulation in the CSF. In the present study, we showed that the overexpression of human tau resulted in its secretion by Hela cells. The main form of tau secreted by these cells was cleaved at the C-terminal. Surprisingly, secreted tau was dephosphorylated at several sites in comparison to intracellular tau which presented a strong immunoreactivity to all phospho-dependent antibodies tested. Our data also revealed that phosphorylation and cleavage of tau favored its secretion by Hela cells. Indeed, the mimicking of phosphorylation at 12 sites known to be phosphorylated in AD enhanced tau secretion. A mutant form of tau truncated at D421, the preferential cleavage site of caspase-3, was also significantly more secreted than wild-type tau. Taken together, our results indicate that hyperphosphorylation and cleavage of tau by favoring its secretion could contribute to the propagation of tau pathology in the brain and its accumulation in the CSF

Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease

Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer’s disease. A fundamental tenet of the amyloid hypothesis of Alzheimer’s disease is that the deposition of amyloid-β precedes and induces the neuronal abnormalities that underlie dementia(1). This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques(2). The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice(3). Here we show that plaques form extraordinarily quickly, over 24 h. Within 1–2 days of a new plaque’s appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology

The influence of synaptic activity on neuronal health

According to the theory of neuronal health, neurons exist in a spectrum of states ranging from highly resilient to vulnerable. An unhealthy neuron may be rendered dysfunctional or non-viable by an insult that would ordinarily be non-toxic to a healthy neuron. Over the years it has become clear that a neuron’s health is subject to dynamic regulation by electrical or synaptic activity. This review highlights recently identified activity dependent signalling events which boost neuronal health through the transcriptional control of pro- and anti-apoptotic genes, the enhancement of antioxidant defences, and the regulation of mitochondrial and neurotrophic factor availability. Furthermore, activity dependent signals have recently been shown to influence a variety of events specific to individual neurodegenerative diseases, which will also be highlighted

Propagation of Tau Pathology in a Model of Early Alzheimer's Disease

SummaryNeurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration