Translation
Advancing (or “translating”) scientific discoveries and mechanistic insights into better therapeutics for major brain disorders is an important goal of the Mucke Lab. This capricious process often makes it necessary to question dogmas and think out of the box. Our studies have challenged earlier views by demonstrating that Tau reduction is well tolerated and by elucidating Tau's role in disease-enabling signaling pathways in Alzheimer’s disease and other brain disorders, including epilepsy and autism [1–6]. These discoveries provided critical guidance in the development of tau-lowering therapeutics [7].
Our preclinical studies also shed light on the intriguing overlap between Alzheimer’s disease and epilepsy [8, 9, 2, 10–14]. Together with clinical collaborators, we showed that, similar to related mouse models, many patients with Alzheimer’s disease have non-convulsive epileptiform activity and that suppressing this activity may have therapeutic benefits [15–17]. These insights have motivated and informed the design of clinical trials targeting network hyperexcitability in early stages of Alzheimer’s disease. We continue to explore the neurobiological impact of drugs that can counteract excitation/inhibition imbalances in neural networks and to identify novel indications for such therapeutics.
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1. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu G-Q, and Mucke L (2007) Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. Science 316: 750–754
2. Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu G-Q, Palop JJ, Noebels JL, and Mucke L (2011) Amyloid-b/Fyn–induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J. Neurosci. 31: 700–711
3. Gheyara A, Ponnusamy R, Djukic B, Craft RJ, Ho K, Guo W, Finucane M, Sanchez P, and Mucke L (2014) Tau reduction prevents disease in a mouse model of Dravet syndrome. Ann. Neurol. 76: 443–456
4. Tai C, Chang C-W, Yu G-Q, Lopez I, Yu X, Wang X, Guo W, and Mucke L (2020) Tau reduction prevents key features of autism in mouse models. Neuron 106: 421–437
5. Das M, Mao W, Shao E, Tamhankar S, Yu G-Q, Yu X, Ho K, Wang X, Wang J, and Mucke L (2021) Interdependence of neural network dysfunction and microglial alterations in Alzheimer’s disease-related models. iScience 24: 103245
6. Shao E, Chang C-W, Li Z, Yu X, Ho K, Zhang M, Wang X, Simms J, Lo I, Speckart J, Holtzman J, Yu G-Q, Roberson ED, and Mucke L (2022) Tau ablation in excitatory neurons and postnatal tau knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model. Sci. Transl. Med. 14: eabm5527
7. Chang C-W, Shao E and Mucke L (2021) Tau: enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies. Science 371: eabb8255
8. Palop JJ, Jones B, Kekonius L, Chin J, Yu G-Q, Raber J, Masliah E, and Mucke L (2003) Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer’s disease-related cognitive deficits. PNAS 100: 9572–9577
9. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu G-Q, Kreitzer A, Finkbeiner S, Noebels JL, and Mucke L (2007) Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55: 697–711
10. Verret L, Mann EO, Hang GB, Barth AMI, Cobos I, Ho K, Devidze N, Masliah E, Kreitzer AC, Mody I, Mucke L, and Palop JJ (2012) Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149: 708–721
11. Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu G-Q, Palop JJ, and Mucke L (2012) Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. PNAS 109: E2895–2903
12. Maeda S, Djukic B, Taneja P, Yu G-Q, Lo I, Davis A, Craft R, Guo W, Wang X, Kim D, Ponnusamy R, Gill TM, Masliah E, and Mucke L (2016) Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice. EMBO Rep. 17: 530–551
13. Johnson ECB, Ho K, Yu G-Q, Das M, Sanchez PE, Djukic B, Lopez I, Yu X, Gill M, Zhang W, Paz JT, Palop JJ, and Mucke L (2020) Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1. Mol. Neurodegener. 15:53, 1–26
14. Palop JJ and Mucke L (2016) Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 17: 777–792
15. Vossel KA, Beagle AJ, Rabinovici GD, Shu H, Lee SE, Naasan G, Hegde M, Cornes SB, Henry ML, Nelson AB, Seeley WW, Geschwind MD, Gorno-Tempini ML, Shih T, Kirsch HE, Garcia PA; Miller BL, and Mucke L (2013) Seizures and epileptiform activity in the early stages of Alzheimer’s disease. JAMA Neurology 70: 1158–1166
16. Miyamoto T, Kim D, Knox JA, Johnson E, and Mucke L (2016) Increasing the receptor tyrosine kinase EphB2 prevents amyloid-β-induced depletion of cell-surface glutamate receptors by a mechanism that requires the PDZ-binding motif of EphB2 and neuronal activity. JBC 291: 1719–1734
17. Vossel K, Ranasinghe KG, Beagle AJ, La A, Pook KA, Castro M, Mizuiri D, Honma SM, Venkateswaran N, Koestler M, Zhang W, Mucke L, Howell MJ, Possin KL, Kramer JH, Boxer AL, Miller BL, Nagarajan SS, and Kirsch HE (2021) Effect of levetiracetam on cognition in patients with Alzheimer disease with and without epileptiform activity – A randomized clinical trial. JAMA Neurol. 78: 1345–1354
“I am really excited about the progress the team is making toward blocking important disease mechanisms and advancing our scientific discoveries toward patients in need and people at risk.”
Lennart Mucke