The Road to Restoring Neural Circuits for the Treatment of Alzheimer's Disease

Overview

Journal Nature

Specialty Science

Date 2016 Nov 11

PMID 27830780

Citations 229

Authors

Rebecca G Canter

Jay Penney

Li-Huei Tsai

Affiliations

Soon will be listed here.

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.

Citing Articles

: a potential trigger of neurodegenerative disease.

Huang Z, Hao M, Shi N, Wang X, Yuan L, Yuan H Front Immunol. 2025; 16:1482033.

PMID: 40028317 PMC: 11867964. DOI: 10.3389/fimmu.2025.1482033.

Mastication Influences Human Brain Anatomy.

Lopez-Chaichio L, Galindo-Moreno P, Padial-Molina M, Gutierrez-Garrido L, Rodriguez-Alvarez R, OValle F J Oral Maxillofac Res. 2025; 15(4):e4.

PMID: 40017684 PMC: 11863650. DOI: 10.5037/jomr.2024.15404.

Predicting the Beneficial Effects of Cognitive Stimulation and Transcranial Direct Current Stimulation in Amnestic Mild Cognitive Impairment with Clinical, Inflammation, and Human Microglia Exposed to Serum as Potential Markers: A Double-Blind....

Alcala-Lozano R, Carmona-Hernandez R, Ocampo-Romero A, Sosa-Millan A, Morelos-Santana E, Abarca D Int J Mol Sci. 2025; 26(4).

PMID: 40004217 PMC: 11855719. DOI: 10.3390/ijms26041754.

TMF Attenuates Cognitive Impairment and Neuroinflammation by Inhibiting the MAPK/NF-κB Pathway in Alzheimer's Disease: A Multi-Omics Analysis.

Liu Y, Xu X, Wu X, Yang G, Luo J, Liang X Mar Drugs. 2025; 23(2).

PMID: 39997198 PMC: 11857128. DOI: 10.3390/md23020074.

The long-term survival and functional maturation of human iNPC-derived neurons in the basal forebrain of cynomolgus monkeys.

Feng S, Zhang T, Ke W, Xiao Y, Guo Z, Lu C Life Med. 2025; 1(2):196-206.

PMID: 39871935 PMC: 11749281. DOI: 10.1093/lifemedi/lnac008.

References

Bramblett G, Goedert M, Jakes R, Merrick S, Trojanowski J, Lee V . Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron. 1993; 10(6):1089-99. DOI: 10.1016/0896-6273(93)90057-x. View

Levy-Lahad E, Wasco W, Poorkaj P, Romano D, Oshima J, Pettingell W . Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995; 269(5226):973-7. DOI: 10.1126/science.7638622. View

McKhann G, Knopman D, Chertkow H, Hyman B, Jack Jr C, Kawas C . The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011; 7(3):263-9. PMC: 3312024. DOI: 10.1016/j.jalz.2011.03.005. View

Frost B, Hemberg M, Lewis J, Feany M . Tau promotes neurodegeneration through global chromatin relaxation. Nat Neurosci. 2014; 17(3):357-66. PMC: 4012297. DOI: 10.1038/nn.3639. View

Mecocci P, MacGarvey U, Beal M . Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol. 1994; 36(5):747-51. DOI: 10.1002/ana.410360510. View

Yankner B, Duffy L, Kirschner D . Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 1990; 250(4978):279-82. DOI: 10.1126/science.2218531. View

Rei D, Mason X, Seo J, Graff J, Rudenko A, Wang J . Basolateral amygdala bidirectionally modulates stress-induced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway. Proc Natl Acad Sci U S A. 2015; 112(23):7291-6. PMC: 4466741. DOI: 10.1073/pnas.1415845112. View

Zhu C, Livote E, Scarmeas N, Albert M, Brandt J, Blacker D . Long-term associations between cholinesterase inhibitors and memantine use and health outcomes among patients with Alzheimer's disease. Alzheimers Dement. 2013; 9(6):733-40. PMC: 3633652. DOI: 10.1016/j.jalz.2012.09.015. View

Lindwall G, Cole R . Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem. 1984; 259(8):5301-5. View

10.

Lambert J, Ibrahim-Verbaas C, Harold D, Naj A, Sims R, Bellenguez C . Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45(12):1452-8. PMC: 3896259. DOI: 10.1038/ng.2802. View

11.

van der Kant R, Goldstein L . Cellular functions of the amyloid precursor protein from development to dementia. Dev Cell. 2015; 32(4):502-15. DOI: 10.1016/j.devcel.2015.01.022. View

12.

Orre M, Kamphuis W, Osborn L, Jansen A, Kooijman L, Bossers K . Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction. Neurobiol Aging. 2014; 35(12):2746-2760. DOI: 10.1016/j.neurobiolaging.2014.06.004. View

13.

Hamelin L, Lagarde J, Dorothee G, Leroy C, Labit M, Comley R . Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging. Brain. 2016; 139(Pt 4):1252-64. DOI: 10.1093/brain/aww017. View

14.

Cacucci F, Yi M, Wills T, Chapman P, OKeefe J . Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model. Proc Natl Acad Sci U S A. 2008; 105(22):7863-8. PMC: 2396558. DOI: 10.1073/pnas.0802908105. View

15.

Duggan S, McCarthy J . Beyond γ-secretase activity: The multifunctional nature of presenilins in cell signalling pathways. Cell Signal. 2015; 28(1):1-11. DOI: 10.1016/j.cellsig.2015.10.006. View

16.

Xia D, Watanabe H, Wu B, Lee S, Li Y, Tsvetkov E . Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. Neuron. 2015; 85(5):967-81. PMC: 4358812. DOI: 10.1016/j.neuron.2015.02.010. View

17.

Sakae N, Liu C, Shinohara M, Frisch-Daiello J, Ma L, Yamazaki Y . ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology. J Neurosci. 2016; 36(13):3848-59. PMC: 4812140. DOI: 10.1523/JNEUROSCI.3757-15.2016. View

18.

Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar M, Okamoto S . Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A. 2013; 110(27):E2518-27. PMC: 3704025. DOI: 10.1073/pnas.1306832110. View

19.

Goate A, Chartier-Harlin M, Mullan M, Brown J, Crawford F, Fidani L . Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991; 349(6311):704-6. DOI: 10.1038/349704a0. View

20.

Busche M, Kekus M, Adelsberger H, Noda T, Forstl H, Nelken I . Rescue of long-range circuit dysfunction in Alzheimer's disease models. Nat Neurosci. 2015; 18(11):1623-30. DOI: 10.1038/nn.4137. View