Amyloid fibrils induce dysfunction of hippocampal glutamatergic silent synapses

Abstract

Silent glutamatergic synapses lacking functional AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate) receptors exist in several brain regions including the hippocampus. Their involvement in the dysfunction of hippocampal glutamatergic transmission in the setting of Alzheimer's disease (AD) is unknown. This study demonstrated a decrease in the percentage of silent synapses in rats microinjected with amyloid fibrils (Aβ ) into the hippocampal CA1. Also, pairing low-frequency electric stimuli failed to induce activation of the hippocampal silent synapses in the modeled rats. Immunoblotting studies revealed a decreased expression of GluR1 subunits in the hippocampal CA1 synaptosomal preparation, indicating a potential reduction in the GluR1 subunits anchoring in postsynaptic density in the modeled rats. We also noted a decreased expression of phosphorylated cofilin, which regulates the function of actin cytoskeleton and receptor trafficking, and reduced expression of the scaffolding protein PSD95 in the hippocampal CA1 synaptosome in rats injected with Aβ . Taken together, this study illustrates dysfunction of hippocampal silent synapse in the rodent model of AD, which might result from the impairments of actin cytoskeleton and postsynaptic scaffolding proteins induced by amyloid fibrils.

Cofilin, a Master Node Regulating Cytoskeletal Pathogenesis in Alzheimer’s Disease

“…In contrast, Heredia and colleagues showed that A␤ 1-40 and A␤ 25-35 fibrils induce the activation of LIMK and resultant cofilin inactivation (phosphorylation), associated with dystrophic neurites in primary neurons [102]. This finding may help to explain the intense pPAK staining surrounding the presumably fibrillar A␤ deposits in AD brains [100], although another recent study found that injection of A␤ 1-40 fibrils into rat brains results in increased activation of cofilin rather than inactivation [103]. Indeed, Ariadna and colleague showed the activation LIMK1 by A␤ 1-42 fibrils, but this was paradoxically associated with increased cofilin activation, suggesting that A␤ 1-42 fibrils may act via bifurcating mechanisms of Rac-LIMK1 activation and perhaps also activation of the SSH1 pathway, the latter perhaps via Rac-mediated activation of NOX and oxidation of 14-3-3 releasing SSH1 [104,105].…”

Impaired Insulin Signaling Alters Mediators of Hippocampal Synaptic Dynamics/Plasticity: A Possible Mechanism of Hyperglycemia-Induced Cognitive Impairment

“…An increased p-cofilin-1/cofilin-1 ratio perturbs dendritic cytoskeletal function and synergizes disease progression via synaptic energy. This augments deficits in hippocampal LTP [ 109 , 110 ] and leads to physiological and neurobehavioral losses [ 111 , 112 ]. Moreover, an imbalanced p-cofilin-1/cofilin-1 ratio leads to the displacement of drebrin from its actin-binding site and impairs dendritic spines/synapses [ 43 ].…”

Is Alzheimer's disease a manifestation of brain quantum decoherence resulting from mitochondrial and microtubular deterioration?

“…Heredia et al (2006) demonstrated that Aβ1-40 and Aβ25-35 fibrils induce the activation of LIMK, which leads to cofilin inactivation. Another study demonstrated, through the injection of Aβ1-40 fibrils into rat brains, that cofilin increased activation rather than inactivation (Bie et al, 2018). Mendoza-Naranjo et al (2012) showed that LIMK1 was activated by Aβ1-42, which is paradoxically related to the increased cofilin activation.…”