Postdoctor, University of Pennsylvania
This study revealed the mysterious interaction between two major AD hall markers.
In the course of Alzheimer’s disease (AD), the accumulation of Aβ plaques is considered an early event while the formation of tau neurofibrillary tangles (NFTs) is thought to be the more proximal cause of neuronal dysfunction and death. The distribution of NFTs in AD is usually restricted in medial temporal lobe at early Braak stages of AD pathology and in later Braak stages, tau pathology spreads outside the temporal lobe into Aβ-rich areas concomitant with significant cognitive dysfunction, lending support to the amyloid cascade hypothesis that Aβ promote NFT formation. However, this hypothesis has not been proven and the underlying mechanisms are enigmatic. Previous studies have attempted to elucidate the interaction between Aβ plaques and NFTs by utilizing transgenic (Tg) mice overexpressing tau with or without MAPT mutations found in rare cases of autosomal dominantly inherited frontotemporal degeneration (FTD). However, it is unclear if these results are applicable to AD since heterologous promoters were used to drive transgene overexpression, and an upregulation or mutation of tau has never been demonstrated in AD. Recently, we established a new paradigm by inducing tau pathologies in wild-type (WT) mice through intracerebral injection of tau fibrils purified from AD brains (AD-tau), which provides a unique opportunity to re-examine the amyloid cascade hypothesis in mice with endogenous levels of tau expression. Here, by injecting AD brain-derived pathological tau (AD-tau) into Aβ plaque-bearing mouse models without overexpression of tau, we recapitulated the formation of three major types of AD-relevant tau pathologies: tau aggregates in dystrophic neurites surrounding Aβ plaques (NPs), AD-like NFTs and neuropil threads (NTs). These distinct tau pathologies show differing temporal onsets and functional consequences on neural activity and behavior. More importantly, we found Aβ plaques created a unique environment that facilitated the rapid amplification of pathological AD-tau seeds into large tau aggregates initially as dystrophic NP tau, followed by the formation and spreading of NFTs and NTs, likely through secondary seeding events. Our study provides significant insight into a new multi-step mechanism underlying Aβ plaque-associated tau pathogenesis, as well as a most pathological relevant AD mouse model to date for identifying potential treatments for this devastating disease.
Abstract: Patients with glioblastoma multiforme, the most aggressive form of glioma, have a median survival of approximately 12 months. Calcium (Ca(2+)) signaling plays an important role in cell proliferation, and some members of the Ca(2+)-permeable transient receptor potential canonical (TRPC) family of channel proteins have demonstrated a role in the proliferation of many types of cancer cells. In this study, we investigated the role of TRPC6 in cell cycle progression and in the development of human glioma.TRPC6 protein and mRNA expression were assessed in glioma (n = 33) and normal (n = 17) brain tissues from patients and in human glioma cell lines U251, U87, and T98G. Activation of TRPC6 channels was tested by platelet-derived growth factor-induced Ca(2+) imaging. The effect of inhibiting TRPC6 activity or expression using the dominant-negative mutant TRPC6 (DNC6) or RNA interference, respectively, was tested on cell growth, cell cycle progression, radiosensitization of glioma cells, and development of xenografted human gliomas in a mouse model. The green fluorescent protein (GFP) and wild-type TRPC6 (WTC6) were used as controls. Survival of mice bearing xenografted tumors in the GFP, DNC6, and WTC6 groups (n = 13, 15, and 13, respectively) was compared using Kaplan-Meier analysis. All statistical tests were two-sided.Functional TRPC6 was overexpressed in human glioma cells. Inhibition of TRPC6 activity or expression attenuated the increase in intracellular Ca(2+) by platelet-derived growth factor, suppressed cell growth and clonogenic ability, induced cell cycle arrest at the G2/M phase, and enhanced the antiproliferative effect of ionizing radiation. Cyclin-dependent kinase 1 activation and cell division cycle 25 homolog C expression regulated the cell cycle arrest. Inhibition of TRPC6 activity also reduced tumor volume in a subcutaneous mouse model of xenografted human tumors (P = .014 vs GFP; P < .001 vs WTC6) and increased mean survival in mice in an intracranial model (P < .001 vs GFP or WTC6).In this preclinical model, TRPC6 channels were essential for glioma development via regulation of G2/M phase transition. This study suggests that TRPC6 might be a new target for therapeutic intervention of human glioma.
Pub.: 18 Jun '10, Pinned: 24 Aug '17
Abstract: Neurotrophin-3 (NT-3) plays numerous important roles in the CNS and the elevation of intracellular Ca(2+) ([Ca(2+)](i)) is critical for these functions of NT-3. However, the mechanism by which NT-3 induces [Ca(2+)](i) elevation remains largely unknown. Here, we found that transient receptor potential canonical (TRPC) 5 protein and TrkC, the NT-3 receptor, exhibited a similar temporal expression in rat hippocampus and cellular colocalization in hippocampal neurons. Stimulation of the neurons by NT-3 induced a nonselective cation conductance and PLCγ-dependent [Ca(2+)](i) elevation, which were both blocked when TRPC5, but not TRPC6 channels, were inhibited. Moreover, the Ca(2+) influx through TRPC5 induced by NT-3 inhibited the neuronal dendritic growth through activation of calmodulin-dependent kinase (CaMK) IIα. In contrast, the Ca(2+) influx through TRPC6 induced by NT-4 promoted the dendritic growth. Thus, TRPC5 acts as a novel and specific mediator for NT-3 to regulate dendrite development through CaMKIIα.
Pub.: 06 Jul '12, Pinned: 24 Aug '17
Abstract: Generation of β-amyloid (Aβ) peptide in Alzheimer’s disease involves cleavage of amyloid precursor protein (APP) by γ-secretase, a protease known to cleave several substrates, including Notch. Finding specific modulators for γ-secretase could be a potential avenue to treat the disease. Here, we report that transient receptor potential canonical (TRPC) 6 specifically interacts with APP leading to inhibition of its cleavage by γ-secretase and reduction in Aβ production. TRPC6 interacts with APP (C99), but not with Notch, and prevents C99 interaction with presenilin 1 (PS1). A fusion peptide derived from TRPC6 also reduces Aβ levels without effect on Notch cleavage. Crossing APP/PS1 mice with TRPC6 transgenic mice leads to a marked reduction in both plaque load and Aβ levels, and improvement in structural and behavioural impairment. Thus, TRPC6 specifically modulates γ-secretase cleavage of APP and preventing APP (C99) interaction with PS1 via TRPC6 could be a novel strategy to reduce Aβ formation.
Pub.: 19 Nov '15, Pinned: 24 Aug '17
Abstract: Filamentous tau aggregates are hallmark lesions in numerous neurodegenerative diseases, including Alzheimer's disease (AD). Cell culture and animal studies showed that tau fibrils can undergo cell-to-cell transmission and seed aggregation of soluble tau, but this phenomenon was only robustly demonstrated in models overexpressing tau. In this study, we found that intracerebral inoculation of tau fibrils purified from AD brains (AD-tau), but not synthetic tau fibrils, resulted in the formation of abundant tau inclusions in anatomically connected brain regions in nontransgenic mice. Recombinant human tau seeded by AD-tau revealed unique conformational features that are distinct from synthetic tau fibrils, which could underlie the differential potency in seeding physiological levels of tau to aggregate. Therefore, our study establishes a mouse model of sporadic tauopathies and points to important differences between tau fibrils that are generated artificially and authentic ones that develop in AD brains.
Pub.: 05 Nov '16, Pinned: 24 Aug '17