The cellular expression and proteolytic processing of the amyloid precursor protein is independent of TDP-43

Hicks, David; Jones, Alys; Pickering‐Brown, Stuart; Hooper, Nigel M.

doi:10.1042/bsr20200435

Cited by 6 publications

(6 citation statements)

References 56 publications

(35 reference statements)

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“…After APP proteolysis, AICD is translocated to the nucleus by binding to adaptor Fe65 and regulates gene transcription [ 49 , 65 ]. Consistent with previous findings [ 20 , 59 ], AICD immunoreactivity recognized by an AICD-specific antibody was mainly observed in the nucleus. Notably, knockout of CHCHD6 in HT-22 cells greatly enhanced the intensity of AICD in the nucleus (Fig.…”

Section: Resultssupporting

confidence: 93%

A CHCHD6–APP axis connects amyloid and mitochondrial pathology in Alzheimer’s disease

et al. 2022

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The mechanistic relationship between amyloid-beta precursor protein (APP) processing and mitochondrial dysfunction in Alzheimer’s disease (AD) has long eluded the field. Here, we report that coiled-coil-helix-coiled-coil-helix domain containing 6 (CHCHD6), a core protein of the mammalian mitochondrial contact site and cristae organizing system, mechanistically connects these AD features through a circular feedback loop that lowers CHCHD6 and raises APP processing. In cellular and animal AD models and human AD brains, the APP intracellular domain fragment inhibits CHCHD6 transcription by binding its promoter. CHCHD6 and APP bind and stabilize one another. Reduced CHCHD6 enhances APP accumulation on mitochondria-associated ER membranes and accelerates APP processing, and induces mitochondrial dysfunction and neuronal cholesterol accumulation, promoting amyloid pathology. Compensation for CHCHD6 loss in an AD mouse model reduces AD-associated neuropathology and cognitive impairment. Thus, CHCHD6 connects APP processing and mitochondrial dysfunction in AD. This provides a potential new therapeutic target for patients.

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Section: Resultssupporting

confidence: 93%

A CHCHD6–APP axis connects amyloid and mitochondrial pathology in Alzheimer’s disease

et al. 2022

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“…Perhaps, in our work, we observe the AICD localization in the nucleolus being more dense than in surrounding karyoplasm. This corresponds to the recent study by Hicks et al, where the predominant localization of AICD in neuron cell nucleolus was shown 42,43 .…”

Section: Discussionsupporting

confidence: 91%

“…We suggest that this is C-terminal AICD fragment, because full-size APP is not expected to enter the nucleus. Recent studies have shown that full-size APP is localized in perikaryon without entering the nucleus 42,43 . However, there are data on interaction and formation of relatively stable APP or APP fragment, exceeding AICD, with Tip60, Fe65, and Pat1a, which is further probably translocated into the nuclear area.…”

Section: Discussionmentioning

confidence: 99%

Expression and Localization of C-APP and N-APP in Peripheral Neurons of Rats and Crayfish After Axotomy

Rodkin¹,

Dzreyan²,

Khaitin³

et al. 2021

Preprint

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Nerve injury induces a cascade of molecular-cellular events, leading to neuronal death or survival, where amyloid precursor protein (APP) and its proteolytic products play an important role. We studied the localization and expression of C-APP and N-APP in rat dorsal root ganglia (DRG) with transected sciatic nerve, axotomized crayfish stretch receptor neuron (SRN) and ventral nerve cord (VNC) ganglia with transected connectives. C-APP and N-APP localized predominantly in neurons, not in glial cells. Axotomy increased C-APP and N-APP expression in rat and crayfish neurons. The expression of APP in crustaceans confirms its conservative nature. In DRG, C-APP level was higher in neuronal nuclei than in cytoplasm in 24 hours post-axotomy. N-APP accumulation was not observed in DRG and crayfish neuronal nuclei. SRN axotomy resulted in C-APP and N-APP accumulation in 4–8 hours in perikaryon and its extensions, but only С-APP accumulated in nuclei. This indicates that not the whole APP, but its C-terminal product, AICD, enters the nucleus. Also, there was high level of C-APP in SRN nucleolus, suggesting possible AICD involvement in rRNA synthesis and ribosome formation. The APP accumulation in transected axons confirms its involvement in injury-induced axonal events.

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“…Data associating TDP-43 with diffuse A pathology irrespective of tau is not reported and indeed, a study examining TDP-43 pathological correlates with antemortem A found no association with global amyloid PET signal 81 . In experimental systems, in vitro TDP-43 does not modulate the expression of APP, nor does APP affect TDP-43 expression 82 , but TDP-43 can accelerate Aβ aggregation in an in vitro seeding assay 83 . In a separate study, injection of TDP-43 into brains of a transgenic mouse model of AD β-amyloidosis altered β-amyloid assembly and increased accumulation of toxic β-Disease Models & Mechanisms • DMM • Accepted manuscript amyloid oligomers 84 .…”

Section: The Synergistic Relationship Between Tau and Tdp-43 Is Specificmentioning

confidence: 97%

TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic Caenorhabditis elegans

Latimer

Stair

Hincks

et al. 2022

Disease Models &Amp; Mechanisms

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While amyloid (A) β and tau aggregates define the neuropathology of Alzheimer's disease (AD), TDP-43 has recently emerged as a co-morbid pathology in over half of patients with AD. Individuals with concomitant Aβ, tau, and TDP-43 pathology experience accelerated cognitive decline and worsened brain atrophy, but the molecular mechanisms of TDP-43 neurotoxicity in AD are unknown. Synergistic interactions among Aβ, tau, and TDP-43 may be responsible for worsened disease outcomes. To study the biology underlying this process, we have developed new models of protein co-morbidity using the simple animal C. elegans. We demonstrate that TDP-43 specifically enhances tau but not Aβ neurotoxicity, resulting in neuronal dysfunction, pathological tau accumulation, and selective neurodegeneration. Furthermore, we find that synergism between tau and TDP-43 is rescued by loss-of-function of the robust tau modifier sut-2. Our results implicate enhanced tau neurotoxicity as the primary driver underlying worsened clinical and neuropathological phenotypes in AD with TDP-43 pathology, and identify cell-type specific sensitivities to co-morbid tau and TDP-43. Determining the relationship between co-morbid TDP-43 and tau is critical to understand and ultimately treat mixed pathology AD.

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The cellular expression and proteolytic processing of the amyloid precursor protein is independent of TDP-43

Cited by 6 publications

References 56 publications

A CHCHD6–APP axis connects amyloid and mitochondrial pathology in Alzheimer’s disease

A CHCHD6–APP axis connects amyloid and mitochondrial pathology in Alzheimer’s disease

Expression and Localization of C-APP and N-APP in Peripheral Neurons of Rats and Crayfish After Axotomy

TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic Caenorhabditis elegans

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