The road to restoring neural circuits for the treatment of Alzheimer's disease

Canter, Rebecca G.; Penney, Jay; Tsai, Li-Huei

doi:10.1038/nature20412

Cited by 565Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchMemory and Neural Mechanisms

The road to restoring neural circuits for the treatment of Alzheimer's disease

Canter, Rebecca G., Penney, Jay, Tsai, Li-Huei·2016·Nature

DOI 10.1038/nature20412

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Abstract

Alzheimer's disease is a progressive loss of memory and cognition, for which there is no cure. Although genetic studies initially suggested a primary role for amyloid-in Alzheimer's disease, treatment strategies targeted at reducing amyloid-have failed to reverse cognitive symptoms. These clinical findings suggest that cognitive decline is the result of a complex pathophysiology and that targeting amyloid-alone may not be sufficient to treat Alzheimer's disease. Instead, a broad outlook on neural-circuit-damaging processes may yield insights into new therapeutic strategies for curing memory loss in the disease.

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Neurons affected by Aβ and p-Tau neurofibrillary pathology in Alzheimer's disease exhibit oxidative damage, impaired calcium handling, defective lysosome function and mitophagy, and reduced DNA repair.
“Neurons affected by Aβ and p-Tau neurofibrillary pathology in AD exhibit oxidative damage, impaired Ca2+ handling, defective lysosome function and mitophagy, and reduced DNA repair (Canter et al., 2016; Fang et al., 2019; Mattson et al., 2018; Polanco et al., 2018).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Canter et al., 2016
All attempts to develop Aβ-targeting drugs to reverse deficits in memory and cognition have ended in failure, despite being successful in reducing the Aβ load.
“all attempts to develop A β -targeting drugs to reverse deficits in memory and cognition have ended in failure, despite being successful in reducing the A β load”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Canter et al., 2016

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Single-cell transcriptomic analysis of Alzheimer’s disease
Mathys, H., Davila-Velderrain, J., Peng, Z., Gao, F., Mohammadi, S., Young, J. Z., Menon, M., He, L., Abdurrob, F., Jiang, X., et al. (2019) · Nature · doi:10.1038/s41586-019-1195-2 · Cited by 2,568 · see citing works
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Gamma frequency entrainment attenuates amyloid load and modifies microglia
Iaccarino, H. F., Singer, A. C., Martorell, A. J., Rudenko, A., Gao, F., Gillingham, T. Z., Mathys, H., Seo, J., Kritskiy, O., Abdurrob, F., et al. (2016) · Nature · doi:10.1038/nature20587 · Cited by 1,328 · see citing works
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APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types
Lin, Y.-T., Seo, J., Gao, F., Feldman, H. M., Wen, H.-L., Penney, J., Cam, H. P., Gjoneska, E., Raja, W. K., Cheng, J., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.008 · Cited by 1,125 · see citing works
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Current understanding of Alzheimer’s disease diagnosis and treatment
Weller, J., & Budson, A. (2018) · F1000Research · doi:10.12688/f1000research.14506.1 · Cited by 1,083 · see citing works
Multi-sensory Gamma Stimulation Ameliorates Alzheimer’s-Associated Pathology and Improves Cognition
Martorell, A. J., Paulson, A. L., Suk, H.-J., Abdurrob, F., Drummond, G. T., Guan, W., Young, J. Z., Kim, D. N.-W., Kritskiy, O., Barker, S. J., et al. (2019) · Cell · doi:10.1016/j.cell.2019.02.014 · Cited by 798 · see citing works
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NAD+ in Brain Aging and Neurodegenerative Disorders
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.001 · Cited by 790 · see citing works
History and progress of hypotheses and clinical trials for Alzheimer’s disease
Liu, P.-P., Xie, Y., Meng, X.-Y., & Kang, J.-S. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0063-8 · Cited by 723 · see citing works
Modeling Alzheimer’s disease with iPSC-derived brain cells
Penney, J., Ralvenius, W. T., & Tsai, L.-H. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0468-3 · Cited by 471 · see citing works
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Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity
Victor, M. B., Leary, N., Luna, X., Meharena, H. S., Scannail, A. N., Bozzelli, P. L., Samaan, G., Murdock, M. H., von Maydell, D., Effenberger, A. H., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.07.005 · Cited by 316 · see citing works
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Fibre-specific white matter reductions in Alzheimer’s disease and mild cognitive impairment
Mito, R., Raffelt, D., Dhollander, T., Vaughan, D. N., Tournier, J.-D., Salvado, O., Brodtmann, A., Rowe, C. C., Villemagne, V. L., & Connelly, A. (2018) · Brain · doi:10.1093/brain/awx355 · Cited by 309 · see citing works
2D versus 3D Human Induced Pluripotent Stem Cell-Derived Cultures for Neurodegenerative Disease Modelling
Centeno, E. G. Z., Cimarosti, H., & Bithell, A. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0258-4 · Cited by 268 · see citing works
Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome
Li, H., Guan, Y., Liang, B., Ding, P., Hou, X., Wei, W., & Ma, Y. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.175091 · Cited by 258 · see citing works
GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease
Bi, D., Wen, L., Wu, Z., & Shen, Y. (2020) · Alzheimer's & Dementia · doi:10.1002/alz.12088 · Cited by 232 · see citing works
HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease
Pao, P.-C., Patnaik, D., Watson, L. A., Gao, F., Pan, L., Wang, J., Adaikkan, C., Penney, J., Cam, H. P., Huang, W.-C., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16361-y · Cited by 216 · see citing works
SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease
Lee, J., Kim, Y., Liu, T., Hwang, Y. J., Hyeon, S. J., Im, H., Lee, K., Alvarez, V. E., McKee, A. C., Um, S., et al. (2018) · Aging Cell · doi:10.1111/acel.12679 · Cited by 213 · see citing works
A Self-Destructive Nanosweeper That Captures and Clears Amyloid β-Peptides
Luo, Q., Lin, Y.-X., Yang, P.-P., Wang, Y., Qi, G.-B., Qiao, Z.-Y., Li, B.-N., Zhang, K., Zhang, J.-P., Wang, L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04255-z · Cited by 191 · see citing works
Shared proteomic effects of cerebral atherosclerosis and Alzheimer’s disease on the human brain
Wingo, A. P., Fan, W., Duong, D. M., Gerasimov, E. S., Dammer, E. B., Liu, Y., Harerimana, N. V., White, B., Thambisetty, M., Troncoso, J. C., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0635-5 · Cited by 161 · see citing works
Casein kinase 1α: biological mechanisms and theranostic potential
Jiang, S., Zhang, M., Sun, J., & Yang, X. (2018) · Cell Communication and Signaling · doi:10.1186/s12964-018-0236-z · Cited by 130 · see citing works
Involvement of the precuneus/posterior cingulate cortex is significant for the development of Alzheimer’s disease: a pet (THK5351, PiB) and resting fMRI study.
Yokoi, T., Watanabe, H., Yamaguchi, H., Bagarinao, E., Masuda, M., Imai, K., Ogura, A., Ohdake, R., Kawabata, K., Hara, K., et al. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00304 · Cited by 116 · see citing works
Glycogen Synthase Kinase 3β: A New Gold Rush in Anti-Alzheimer’s Disease Multitarget Drug Discovery?: Miniperspective
De Simone, A., Tumiatti, V., Andrisano, V., & Milelli, A. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00931 · Cited by 110 · see citing works
Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease
La Barbera, L., Vedele, F., Nobili, A., Krashia, P., Spoleti, E., Latagliata, E. C., Cutuli, D., Cauzzi, E., Marino, R., Viscomi, M. T., et al. (2021) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2021.102031 · Cited by 98 · see citing works
Fermented Soy Products: Beneficial Potential in Neurodegenerative Diseases
Jang, C. H., Oh, J., Lim, J. S., Kim, H. J., & Kim, J.-S. (2021) · Foods · doi:10.3390/foods10030636 · Cited by 100 · see citing works
Physiological Roles of β-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology
Cai, W., Li, L., Sang, S., Pan, X., & Zhong, C. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-022-00985-9 · Cited by 83 · see citing works
Dopamine loss alters the hippocampus-nucleus accumbens synaptic transmission in the Tg2576 mouse model of Alzheimer’s disease
Cordella, A., Krashia, P., Nobili, A., Pignataro, A., La Barbera, L., Viscomi, M. T., Valzania, A., Keller, F., Ammassari-Teule, M., Mercuri, N. B., et al. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.05.006 · Cited by 82 · see citing works
Deep learning-based identification of genetic variants: application to Alzheimer’s disease classification
Jo, T., Nho, K., Bice, P., Saykin, A. J., & Initiative, F. T. A. D. N. (2022) · Briefings in Bioinformatics · doi:10.1093/bib/bbac022 · Cited by 80 · see citing works
High prevalence of focal and multi-focal somatic genetic variants in the human brain
Keogh, M. J., Wei, W., Aryaman, J., Walker, L., van den Ameele, J., Coxhead, J., Wilson, I., Bashton, M., Beck, J., West, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06331-w · Cited by 74 · see citing works
Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease
Vyas, Y., Montgomery, J. M., & Cheyne, J. E. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00266 · Cited by 66 · see citing works
Osteocalcin ameliorates cognitive dysfunctions in a mouse model of Alzheimer’s Disease by reducing amyloid β burden and upregulating glycolysis in neuroglia
Shan, C., Zhang, D., Ma, D.-N., Hou, Y.-F., Zhuang, Q.-Q., Gong, Y.-L., Sun, L.-H., Zhao, H.-Y., Tao, B., Yang, Y.-Y., et al. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01343-y · Cited by 53 · see citing works
Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy
Zagórska, A., & Jaromin, A. (2020) · Molecules · doi:10.3390/molecules25153337 · Cited by 51 · see citing works
Cognitive-enhancing and ameliorative effects of acanthoside B in a scopolamine-induced amnesic mouse model through regulation of oxidative/inflammatory/cholinergic systems and activation of the TrkB/CREB/BDNF pathway
Karthivashan, G., Kweon, M.-H., Park, S.-Y., Kim, J.-S., Kim, D.-H., Ganesan, P., & Choi, D.-K. (2019) · Food and Chemical Toxicology · doi:10.1016/j.fct.2019.04.062 · Cited by 34 · see citing works
Is It the Twilight of BACE1 Inhibitors?
Hrabinova, M., Pejchal, J., Kucera, T., Jun, D., Schmidt, M., & Soukup, O. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200503023323 · Cited by 28 · see citing works
Versatile nanomaterials for Alzheimer’s disease: Pathogenesis inspired disease-modifying therapy
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Neurexin‐β mediates the synaptogenic activity of amyloid precursor protein
Cvetkovska, V., Ge, Y., Xu, Q., Li, S., Zhang, P., & Craig, A. M. (2022) · The Journal of Neuroscience · doi:10.1523/jneurosci.0511-21.2022 · Cited by 17 · see citing works

[The incidence of reversible dementia in 145 patients referred on suspicion of dementia].
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Evaluating the Association between Diabetes, Cognitive Decline and Dementia
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Vitamin D, Alzheimer’s disease and related dementia
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Diet and Nutrition in Dementia and Cognitive Decline
Kolasa, K. M. (2015) · Journal of Nutrition Education and Behavior · doi:10.1016/j.jneb.2015.02.011 · Cited by 77 · see citing works
Disregarding hearing loss leads to overestimation of age-related cognitive decline
Guerreiro, M. J. S., & Gerven, P. W. M. V. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.05.001 · Cited by 43 · see citing works

Authors: Canter, R. G., Penney, J., & Tsai, L.-H.
Affiliations: Massachusetts Institute of Technology (US)
Broad Institute (US)
Corresponding author: Tsai, Li-Huei
ORCID: Penney, Jay
Tsai, Li-Huei
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2016-11
Volume: 539
Issue: 7628
Pages: 187-196
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature20412
OpenAlex: W2556389549
Semantic Scholar: 9e25384fef7a1e87bd206f4071f03b75eb515c8c
Cited by: 565
References: 153
Citations by year: 2026: 22 · 2025: 56 · 2024: 53 · 2023: 54 · 2022: 78 · 2021: 82 · 2020: 80 · 2019: 63 · 2018: 43 · 2017: 32 · 2016: 1
FWCI: 5.43
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
IslandScholar (University of Prince Edward Island) (submittedVersion)
Funders: JPB Foundation
National Institutes of Health (1rf1ag042978-01)
National Institute on Aging (RF1AG047661, RF1-AG042978)
National Institute of Neurological Disorders and Stroke (R01NS078839, R01NS051874)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords: Alzheimer's disease, amyloid, anti-amyloid therapy, cognitive decline, memory loss, treatment options, pathophysiology
MeSH terms: Alzheimer Disease, Animals, Cognition, Humans, Neural Pathways, Synapses, Amyloid beta-Peptides, Disease Progression

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The road to restoring neural circuits for the treatment of Alzheimer's disease

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