Targeting synapse function and loss for treatment of neurodegenerative diseases

Wilson, D. M. et al. Hallmarks of neurodegenerative diseases. Cell 186, 693–714 (2023).

Article  CAS  PubMed  Google Scholar 

Terry, R. D. et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991).

Article  CAS  PubMed  Google Scholar 

DeKosky, S. T. & Scheff, S. W. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann. Neurol. 27, 457–464 (1990).

Article  CAS  PubMed  Google Scholar 

Blennow, K., Bogdanovic, N., Alafuzoff, I., Ekman, R. & Davidsson, P. Synaptic pathology in Alzheimer’s disease: relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele. J. Neural Transm. 103, 603–618 (1996).

Article  CAS  PubMed  Google Scholar 

Scheff, S. W., Price, D. A., Schmitt, F. A., DeKosky, S. T. & Mufson, E. J. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68, 1501–1508 (2007).

Article  CAS  PubMed  Google Scholar 

Südhof, T. C. Towards an understanding of synapse formation. Neuron 100, 276–293 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Sheng, M. & Hoogenraad, C. C. The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu. Rev. Biochem. 76, 823–847 (2007).

Article  CAS  PubMed  Google Scholar 

Dejanovic, B. et al. Palmitoylation of gephyrin controls receptor clustering and plasticity of GABAergic synapses. PLoS Biol. 12, e1001908 (2014).

Article  PubMed  PubMed Central  Google Scholar 

Avery, M. C. & Krichmar, J. L. Neuromodulatory systems and their interactions: a review of models, theories, and experiments. Front. Neural Circuits 11, 108 (2017).

Article  PubMed  PubMed Central  Google Scholar 

Ferreira-Vieira, T. H., Guimaraes, I. M., Silva, F. R. & Ribeiro, F. M. Alzheimer’s disease: targeting the cholinergic system. Curr. Neuropharmacol. 14, 101–115 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Allen, N. J. & Eroglu, C. Cell biology of astrocyte-synapse interactions. Neuron 96, 697–708 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005).

Article  CAS  PubMed  Google Scholar 

Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).

Article  CAS  PubMed  Google Scholar 

Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).

Article  CAS  PubMed  Google Scholar 

Chung, W.-S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394–400 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lee, J.-H. et al. Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis. Nature 590, 612–617 (2021).

Article  CAS  PubMed  Google Scholar 

Hammond, T. R., Marsh, S. E. & Stevens, B. Immune signaling in neurodegeneration. Immunity 50, 955–974 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bohlen, C. J., Friedman, B. A., Dejanovic, B. & Sheng, M. Microglia in brain development, homeostasis, and neurodegeneration. Annu. Rev. Genet. 53, 263–288 (2019).

Article  CAS  PubMed  Google Scholar 

Dejanovic, B. et al. Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies. Neuron 100, 1322–1336.e7 (2018).

Article  CAS  PubMed  Google Scholar 

Dejanovic, B. et al. Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models. Nat. Aging 2, 837–850 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wu, T. et al. Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy. Cell Rep. 28, 2111–2123.e6 (2019).

Article  CAS  PubMed  Google Scholar 

Zhang, J. et al. Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency. Nature 588, 459–465 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lui, H. et al. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165, 921–935 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vasek, M. J. et al. A complement–microglial axis drives synapse loss during virus-induced memory impairment. Nature 534, 538–543 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, aad8373 (2016).

Article  Google Scholar 

Werneburg, S. et al. Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease. Immunity 52, 167–182.e7 (2020).

Article  CAS  PubMed  Google Scholar 

Comer, A. L. et al. Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction. PLoS Biol. 18, e3000604 (2020).

Article  PubMed  PubMed Central  Google Scholar 

Wilton, D. K. et al. Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease. Nat. Med. https://doi.org/10.1038/s41591-023-02566-3 (2023).

Yilmaz, M. et al. Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice. Nat. Neurosci. 24, 214–224 (2021).

Article  CAS  PubMed  Google Scholar 

Zhou, J. et al. The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration. Sci. Transl Med. 15, eadf0141 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hansen, D. V., Hanson, J. E. & Sheng, M. Microglia in Alzheimer’s disease. J. Cell Biol. 217, 459–472 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Srinivasan, K. et al. Alzheimer’s patient microglia exhibit enhanced aging and unique transcriptional activation. Cell Rep. 31, 107843 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Smajić, S. et al. Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain 145, awab446 (2021).

Google Scholar 

Menden, K. et al. Integrated multi-omics analysis reveals common and distinct dysregulated pathways for genetic subtypes of frontotemporal dementia. Preprint at bioRxiv https://doi.org/10.21203/rs.3.rs-153135/v1 (2021).

Limone, F. et al. Single-nucleus sequencing reveals enriched expression of genetic risk factors sensitises motor neurons to degeneration in ALS. Preprint at bioRxiv https://doi.org/10.1101/2021.07.12.452054 (2021).

Wilton, D. K., Dissing-Olesen, L. & Stevens, B. Neuron-glia signaling in synapse elimination. Annu. Rev. Neurosci. 42, 107–127 (2019).

Article  CAS  PubMed  Google Scholar 

Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yun, S. P. et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat. Med. 24, 931–938 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liddelow, S. A. & Barres, B. A. Reactive astrocytes: production, function, and therapeutic potential. Immunity 46, 957–967 (2017).

Article  CAS  PubMed 

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