Aβ mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease

Abstract

Dendritic spine loss is recognized as an early feature of Alzheimer's disease (AD), but the underlying mechanisms are poorly understood. Dendritic spine structure is defined by filamentous actin (F-actin) and we observed depolymerization of synaptosomal F-actin accompanied by increased globular-actin (G-actin) at as early as 1 month of age in a mouse model of AD (APPswe/PS1ΔE9, male mice). This led to recall deficit after contextual fear conditioning (cFC) at 2 months of age in APPswe/PS1ΔE9 male mice, which could be reversed by the actin-polymerizing agent jasplakinolide. Further, the F-actin-depolymerizing agent latrunculin induced recall deficit after cFC in WT mice, indicating the importance of maintaining F-/G-actin equilibrium for optimal behavioral response. Using direct stochastic optical reconstruction microscopy (dSTORM), we show that F-actin depolymerization in spines leads to a breakdown of the nano-organization of outwardly radiating F-actin rods in cortical neurons from APPswe/PS1ΔE9 mice. Our results demonstrate that synaptic dysfunction seen as F-actin disassembly occurs very early, before onset of pathological hallmarks in AD mice, and contributes to behavioral dysfunction, indicating that depolymerization of F-actin is causal and not consequent to decreased spine density. Further, we observed decreased synaptosomal F-actin levels in postmortem brain from mild cognitive impairment and AD patients compared with subjects with normal cognition. F-actin decrease correlated inversely with increasing AD pathology (Braak score, Aβ load, and tangle density) and directly with performance in episodic and working memory tasks, suggesting its role in human disease pathogenesis and progression.SIGNIFICANCE STATEMENT Synaptic dysfunction underlies cognitive deficits in Alzheimer's disease (AD). The cytoskeletal protein actin plays a critical role in maintaining structure and function of synapses. Using cultured neurons and an AD mouse model, we show for the first time that filamentous actin (F-actin) is lost selectively from synapses early in the disease process, long before the onset of classical AD pathology. We also demonstrate that loss of synaptic F-actin contributes directly to memory deficits. Loss of synaptosomal F-actin in human postmortem tissue correlates directly with decreased performance in memory test and inversely with AD pathology. Our data highlight that synaptic cytoarchitectural changes occur early in AD and they may be targeted for the development of therapeutics.

Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies

“…Iqgap1, Iqgap2, Iqsec2, Kalirin, and Trio regulate Rho family GTPases and hence play a pivotal role in the dynamics of the F-actin cytoskeleton in spines (Spence and Soderling, 2015). Loss of these GTPase regulators could provide a molecular explanation for why actin is compromised in spines of AD patients (Kommaddi et al, 2018). Because these proteins normally regulate dendritic spine integrity and synapse density as well as synaptic signaling, the PSD-specific depletion of Iqgap1, Iqgap2, Iqsec2, Kalirin, and Trio could contribute to synaptic dysfunction and cognitive impairment in AD, as evidenced by synaptic and/or cognitive deficits upon deletion of these genes (Cahill et al, 2009;Elagabani et al, 2016;Gao et al, 2011;Herring and Nicoll, 2016).…”

Neuroprotective Effects of Quercetin in Alzheimer’s Disease

“…Alzheimer's disease (AD) contributes to 60-80% of total dementia cases, and it mostly affects elder people (65 years of age or older) [1]. The pathogenesis of AD is typically associated with the accumulation of amyloid-β (Aβ) aggregates and the hyperphosphorylation of tau proteins, leading to neurofibrillary tangles (NFTs) and synaptic dysfunction [2][3][4]. Around 35.6 million people worldwide are estimated to be affected with AD, with a prevalence rate of 4.6 million new cases each year.…”

Role of actin in organelle trafficking in neurons

“…The F‐actin disassembly in these disease models could additionally affect actin‐dependent positioning of organelles at dendritic spines as described in the sections above. Additionally, F‐actin disassembly in dendritic spines seen in an Alzheimer's disease model precedes synapse dysfunction, suggesting a role for actin in the progression of phenotypes in Alzheimer's disease (Kommaddi et al, ). A similar decrease in F‐actin/G‐actin ratio was also seen in postmortem tissues of patients with mild cognitive impairment or Alzheimer's disease (Kommaddi et al, ).…”