β-secretase Inhibition Prevents Structural Spine Plasticity Deficits in Mice

Overview

Journal Front Aging Neurosci

Specialty Geriatrics

Date 2022 Aug 8

PMID 35936777

Authors

Tanja Blume

Severin Filser

Carmelo Sgobio

Finn Peters

Ulf Neumann

Derya Shimshek

Takashi Saito

Takaomi C Saido

Matthias Brendel

Jochen Herms

Affiliations

Soon will be listed here.

Abstract

All clinical BACE1-inhibitor trials for the treatment of Alzheimer's Disease (AD) have failed due to insufficient efficacy or side effects like worsening of cognitive symptoms. However, the scientific evidence to date suggests that BACE1-inhibition could be an effective preventative measure if applied prior to the accumulation of amyloid-beta (Aβ)-peptide and resultant impairment of synaptic function. Preclinical studies have associated BACE1-inhibition-induced cognitive deficits with decreased dendritic spine density. Therefore, we investigated dose-dependent effects of BACE1-inhibition on hippocampal dendritic spine dynamics in an APP knock-in mouse line for the first time. We conducted two-photon microscopy in the hippocampal CA1 neurons in 3.5-month-old GFP-M mice over 6 weeks to monitor the effect of potential preventive treatment with a high and low dose of the BACE1-inhibitor NB-360 on dendritic spine dynamics. Structural spine plasticity was severely impaired in untreated GFP-M mice, although spines were not yet showing signs of degeneration. Prolonged high-dose BACE1-inhibition significantly enhanced spine formation, improving spine dynamics in the AD mouse model. We conclude that in an early AD stage characterized by low Aβ-accumulation and no irreversible spine loss, BACE1-inhibition could hold the progressive synapse loss and cognitive decline by improving structural spine dynamics.

Citing Articles

The senile plaque: Morphological differences in APP knock-in mice brains by fixatives.

Yoshimura R, Miyasaka T, Funamoto S, Saito T, Saido T, Ikegawa M Brain Behav. 2023; 13(4):e2953.

PMID: 36879381 PMC: 10097081. DOI: 10.1002/brb3.2953.

References

Masuda A, Kobayashi Y, Kogo N, Saito T, Saido T, Itohara S . Cognitive deficits in single App knock-in mouse models. Neurobiol Learn Mem. 2016; 135:73-82. DOI: 10.1016/j.nlm.2016.07.001. View

Bourne J, Harris K . Do thin spines learn to be mushroom spines that remember?. Curr Opin Neurobiol. 2007; 17(3):381-6. DOI: 10.1016/j.conb.2007.04.009. View

Hardy J, Selkoe D . The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002; 297(5580):353-6. DOI: 10.1126/science.1072994. View

Holtmaat A, Svoboda K . Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci. 2009; 10(9):647-58. DOI: 10.1038/nrn2699. View

Matsuzaki M, Honkura N, Ellis-Davies G, Kasai H . Structural basis of long-term potentiation in single dendritic spines. Nature. 2004; 429(6993):761-6. PMC: 4158816. DOI: 10.1038/nature02617. View

Haass C, Selkoe D . Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007; 8(2):101-12. DOI: 10.1038/nrm2101. View

Knopman D . Lowering of Amyloid-Beta by β-Secretase Inhibitors - Some Informative Failures. N Engl J Med. 2019; 380(15):1476-1478. DOI: 10.1056/NEJMe1903193. View

Yang G, Pan F, Gan W . Stably maintained dendritic spines are associated with lifelong memories. Nature. 2009; 462(7275):920-4. PMC: 4724802. DOI: 10.1038/nature08577. View

Feng G, Mellor R, Bernstein M, Nguyen Q, Wallace M, Nerbonne J . Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron. 2000; 28(1):41-51. DOI: 10.1016/s0896-6273(00)00084-2. View

10.

Latif-Hernandez A, Sabanov V, Ahmed T, Craessaerts K, Saito T, Saido T . The two faces of synaptic failure in App knock-in mice. Alzheimers Res Ther. 2020; 12(1):100. PMC: 7445922. DOI: 10.1186/s13195-020-00667-6. View

11.

Tackenberg C, Ghori A, Brandt R . Thin, stubby or mushroom: spine pathology in Alzheimer's disease. Curr Alzheimer Res. 2009; 6(3):261-8. DOI: 10.2174/156720509788486554. View

12.

Koffie R, Meyer-Luehmann M, Hashimoto T, Adams K, Mielke M, Garcia-Alloza M . Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci U S A. 2009; 106(10):4012-7. PMC: 2656196. DOI: 10.1073/pnas.0811698106. View

13.

Engert F, Bonhoeffer T . Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature. 1999; 399(6731):66-70. DOI: 10.1038/19978. View

14.

McClelland J, McNaughton B, OReilly R . Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol Rev. 1995; 102(3):419-457. DOI: 10.1037/0033-295X.102.3.419. View

15.

Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82(4):239-59. DOI: 10.1007/BF00308809. View

16.

Nagerl U, Eberhorn N, Cambridge S, Bonhoeffer T . Bidirectional activity-dependent morphological plasticity in hippocampal neurons. Neuron. 2004; 44(5):759-67. DOI: 10.1016/j.neuron.2004.11.016. View

17.

Zhu K, Xiang X, Filser S, Marinkovic P, Dorostkar M, Crux S . Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibition Impairs Synaptic Plasticity via Seizure Protein 6. Biol Psychiatry. 2017; 83(5):428-437. DOI: 10.1016/j.biopsych.2016.12.023. View

18.

Klevanski M, Herrmann U, Weyer S, Fol R, Cartier N, Wolfer D . The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior. J Neurosci. 2015; 35(49):16018-33. PMC: 6605503. DOI: 10.1523/JNEUROSCI.2009-15.2015. View

19.

Heine M, Groc L, Frischknecht R, Beique J, Lounis B, Rumbaugh G . Surface mobility of postsynaptic AMPARs tunes synaptic transmission. Science. 2008; 320(5873):201-5. PMC: 2715948. DOI: 10.1126/science.1152089. View

20.

Pigoni M, Wanngren J, Kuhn P, Munro K, Gunnersen J, Takeshima H . Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons. Mol Neurodegener. 2016; 11(1):67. PMC: 5053352. DOI: 10.1186/s13024-016-0134-z. View