Regulated cell death and its role in Alzheimer’s disease and amyotrophic lateral sclerosis

Thal, Dietmar Rudolf; Gawor, Klara; Moonen, Sebastiaan

doi:10.1007/s00401-024-02722-0

Cited by 5 publications

(2 citation statements)

References 229 publications

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“…A critical note remains that cell death pathway molecules are multifunctional and can be involved in an array of mechanisms leading to protection or cell death. The following years will teach to what extent necroptosis is necessary and sufficient for neuronal loss in AD or whether it is the culmination of varying cell death pathways and PANoptosis that determines the outcome of this devastating disease [ 161 ].…”

Section: Discussionmentioning

confidence: 99%

The necroptosis cell death pathway drives neurodegeneration in Alzheimer’s disease

Balusu,

De Strooper

2024

Acta Neuropathol

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Although apoptosis, pyroptosis, and ferroptosis have been implicated in AD, none fully explains the extensive neuronal loss observed in AD brains. Recent evidence shows that necroptosis is abundant in AD, that necroptosis is closely linked to the appearance of Tau pathology, and that necroptosis markers accumulate in granulovacuolar neurodegeneration vesicles (GVD). We review here the neuron-specific activation of the granulovacuolar mediated neuronal-necroptosis pathway, the potential AD-relevant triggers upstream of this pathway, and the interaction of the necrosome with the endo-lysosomal pathway, possibly providing links to Tau pathology. In addition, we underscore the therapeutic potential of inhibiting necroptosis in neurodegenerative diseases such as AD, as this presents a novel avenue for drug development targeting neuronal loss to preserve cognitive abilities. Such an approach seems particularly relevant when combined with amyloid-lowering drugs.

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Section: Discussionmentioning

confidence: 99%

The necroptosis cell death pathway drives neurodegeneration in Alzheimer’s disease

Balusu,

De Strooper

2024

Acta Neuropathol

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“…Consistent with reported functions of LINGO1/LINGO2, downregulation of LINGO2 rescued neurite outgrowth deficits in APP V717I neurons. In addition, the LINGO2 KD reversed several transcriptome signatures in APP V717I neurons to Ctrl levels, including those related to synaptic function as well as apoptosis and cellular senescence, which are activated in AD in addition to alternative cell death-associated pathways [ 24 , 70 ]. Recent work demonstrated that AD patient brains contain a significantly higher number of neurons that express senescence marker, and cultured AD neurons (iNs) displayed a senescence-like state with a senescence-associated pro-inflammatory phenotype [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Xenografted human iPSC-derived neurons with the familial Alzheimer’s disease APPV717I mutation reveal dysregulated transcriptome signatures linked to synaptic function and implicate LINGO2 as a disease signaling mediator

Qu,

Lam,

McInvale

et al. 2024

Acta Neuropathol

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Alzheimer’s disease (AD) is the most common cause of dementia, and disease mechanisms are still not fully understood. Here, we explored pathological changes in human induced pluripotent stem cell (iPSC)-derived neurons carrying the familial AD APPV717I mutation after cell injection into the mouse forebrain. APPV717I mutant iPSCs and isogenic controls were differentiated into neurons revealing enhanced Aβ42 production, elevated phospho-tau, and impaired neurite outgrowth in APPV717I neurons. Two months after transplantation, APPV717I and control neural cells showed robust engraftment but at 12 months post-injection, APPV717I grafts were smaller and demonstrated impaired neurite outgrowth compared to controls, while plaque and tangle pathology were not seen. Single-nucleus RNA-sequencing of micro-dissected grafts, performed 2 months after cell injection, identified significantly altered transcriptome signatures in APPV717I iPSC-derived neurons pointing towards dysregulated synaptic function and axon guidance. Interestingly, APPV717I neurons showed an increased expression of genes, many of which are also upregulated in postmortem neurons of AD patients including the transmembrane protein LINGO2. Downregulation of LINGO2 in cultured APPV717I neurons rescued neurite outgrowth deficits and reversed key AD-associated transcriptional changes related but not limited to synaptic function, apoptosis and cellular senescence. These results provide important insights into transcriptional dysregulation in xenografted APPV717I neurons linked to synaptic function, and they indicate that LINGO2 may represent a potential therapeutic target in AD.

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Regulated cell death in neurodegeneration: pathways and therapeutic horizons

Thal,

De Strooper

2024

Acta Neuropathol

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Regulated cell death and its role in Alzheimer’s disease and amyotrophic lateral sclerosis

Cited by 5 publications

References 229 publications

The necroptosis cell death pathway drives neurodegeneration in Alzheimer’s disease

The necroptosis cell death pathway drives neurodegeneration in Alzheimer’s disease

Xenografted human iPSC-derived neurons with the familial Alzheimer’s disease APPV717I mutation reveal dysregulated transcriptome signatures linked to synaptic function and implicate LINGO2 as a disease signaling mediator

Regulated cell death in neurodegeneration: pathways and therapeutic horizons

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