β-Amyloid fibrils induce tau phosphorylation and loss of microtubule binding

Busciglio, Jorge; Lorenzo, Alfredo; Yeh, John; Yankner, Bruce A.

doi:10.1016/0896-6273(95)90232-5

Cited by 577 publications

(428 citation statements)

References 53 publications

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“…Therefore, initial deposition of A␤1-42 is a necessary early pathological process, but it is not sufficient to develop mature amyloid plaques unless succeeded by further deposition of A␤1-40. Although A␤1-42 failed to form fibrils in vivo as we observed in the present experimental animal system, it spontaneously assembled into fibrils after preincubation in vitro, and this is consistent in turn with previous in vitro studies (Lorenzo and Yankner, 1994;Ma et al, 1994;Buscioglio et al, 1995). The mechanism that accounts for this differential assembly of A␤1-42 into fibrils in vitro but not in vivo is currently unknown, but it is plausible that a factor or factors exist in the rat brain that inhibit the assembly of A␤1-42 into amyloid fibrils.…”

Section: Discussionsupporting

confidence: 80%

Amyloid β-Protein (Aβ) 1–40 But Not Aβ1–42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain

et al. 1997

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Two major C-terminal variants ending at Val40 and Ala42 constitute the majority of amyloid ␤-protein (A␤), which undergoes postsecretory aggregation and deposition in the Alzheimer disease (AD) brain. To probe the differential pathobiology of the two A␤ variants, we used an in vivo paradigm in which freshly solubilized A␤1-40 or A␤1-42 was injected into rat brains, followed by examination using Congo red birefringence, A␤ immunohistochemistry, and electron microscopy. In the rat brain, soluble A␤ 1-40 and A␤1-42 formed aggregates, and the A␤1-40 but not the A␤1-42 aggregates showed Congo red birefringence. Electron microscopy revealed that the A␤1-40 aggregates contained fibrillar structures similar to the amyloid fibrils of AD, whereas the A␤1-42 aggregates contained nonfibrillar amorphous material. Preincubation of A␤1-42 solution in vitro led to the formation of birefringent aggregates, and after injection of the preincubated A␤1-42, the aggregates remained birefringent in the rat brain. Thus, a factor or factors might exist in the rat brain that inhibit the fibrillar assembly of soluble A␤1-42. To analyze the postsecretory processing of A␤, we used the same in vivo paradigm and showed that A␤1-40 and A␤1-42 were processed at their N termini to yield variants starting at pyroglutamate, and at their C termini to yield variants ending at Val40 and at Val39. Thus the normal rat brain could produce enzymes that mediate the conversion of A␤ 1-40/1-42 into processed variants similar to those in AD. This experimental paradigm may facilitate efforts to elucidate mechanisms of A␤ deposition evolving into amyloid plaques in AD.

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Section: Discussionsupporting

confidence: 80%

Amyloid β-Protein (Aβ) 1–40 But Not Aβ1–42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain

et al. 1997

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“…The high ratio of Tau2-positive neurons to TUNEL-stained nuclei is considered to be due to neuronal loss caused by late stage NFT because Tau2 tended to label typical tangle-shaped NFT. Amyloid fibril formation has been shown to be one factor associated with tau protein phosphorylation in AD [39], and early tau deposition is regulated by phosphorylated map kinase [16]. Apoptosis is essentially an intrinsic mechanism, so that factors (reviewed in [15]) merely accelerate or recover the process.…”

Section: Resultsmentioning

confidence: 99%

Association of phosphorylation site of tau protein with neuronal apoptosis in Alzheimer's disease

Kobayashi

Nakano

Hayashi

et al. 2003

Journal of the Neurological Sciences

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In addition to neuritic changes and amyloid deposits, neuronal and glial cell apoptosis is an important pathological feature of Alzheimer's disease (AD). Several factors have been postulated as causes or triggers of cellular apoptotic change. This study focused on a quantifiable relationship between phosphorylation sites of tau protein in the neurofibrillary tangles (NFT) and neuronal apoptosis. Five monoclonal anti-tau antibodies (AT180, AT8, HT7, Tau2 and Tau5) for NFT labeling and TdT-mediated UTP nick-end labeling (TUNEL) for localizing apoptotic change were employed. TUNEL-stained neuronal nuclei showed significantly high density in the entorhinal cortex, cornu ammonis (CA) and the parietal cortex. In all regions, density of TUNEL-stained neuronal nuclei showed significantly direct correlation with that of AT8-, AT180-and Tau2-positive neurons. Correlation of TUNEL-stained neuronal nuclei with tau-positive neurons differed depending on the cerebral regions. Density of TUNEL-stained neuronal nuclei showed inverse correlation with that of both AT8-positive and Gallyas-stained NFT in the CA and showed significantly direct correlation with AT8-and HT7-positive neurons in the frontal cortex. Density of tau-positive and Gallyas-stained NFT was higher than that of TUNEL-stained nuclei. We conclude that phosphorylation sites of tau, 159-163 and 202-205, are probably associated with neuronal apoptosis and apoptotic change follows abnormal phosphorylation of tau.2 Introduction Apoptosis, a programmed cell death by intrinsic mechanism to regulate cell population, has been shown to occur extensively in brains from patients with Alzheimer's disease (AD). In addition to neurofibrillary tangles (NFT) and beta amyloid protein (BAP) deposits, abundant apoptotic neuronal and glial cells are another pathological hallmark of AD [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Abnormal phosphorylation of the tau protein that leads to NFT formation, BAP deposits, high concentration of amyloid precursor protein (APP), caspase-3, the presenilin 1 and 2 gene and nitric oxide are considered to be important triggers of neuronal and glial apoptosis . Since NFT are present in the neuronal cytoplasm, NFT and neuronal apoptosis have been considered to be intimately associated with each other. To the best of our knowledge, 13 studies, ten in vivo [1, 3, 5, 7, 8-10, 13, 16, 18] and three in vitro [15,18,22], have addressed the relationship between NFT formation and neuronal apoptosis. However, it is still unclear whether neuronal apoptosis is a result or cause of abnormal phosphorylation of tau.Tau immunohistochemistry has differentiated pretangle neurons, known as stage 0 tangles [26][27], from argyrophilic NFT, and phosphorylation sites of the amino acid sequence of tau molecules have been analyzed in AD brains [28][29]. The pretangle neurons are believed to occur in the early stage and may disappear in the late stage of AD with some of them remaining unchanged. A recent study has demonstrated that neurons with ...

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“…Aβ induces tau hyperphosphorylation, aggregation, and enhances tau toxicity. Treating cell cultures with multiple forms of Aβ, including soluble Aβ1-42 [40], Aβ oligomer [41], and Aβ fibril [42] induces tau hyperphosphorylation. Aβ-induced tau hyperphosphorylation consequently caused microtubule disassembly [41,43], reduction of total soluble tau and an increase in tau fragments [44], missorting of tau into dendritic areas [41], activation of the nuclear transcription factor of activated T cells' apoptotic pathways [45,46], and cell toxicity [41,44].…”

Section: Challenges In Targeting Amyloidmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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β-Amyloid fibrils induce tau phosphorylation and loss of microtubule binding

Cited by 577 publications

References 53 publications

Amyloid β-Protein (Aβ) 1–40 But Not Aβ1–42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain

Amyloid β-Protein (Aβ) 1–40 But Not Aβ1–42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain

Association of phosphorylation site of tau protein with neuronal apoptosis in Alzheimer's disease

Biometals and Their Therapeutic Implications in Alzheimer's Disease

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