Elevated amyloid beta disrupts the nanoscale organization and function of synaptic vesicle pools in hippocampal neurons

Abstract

Alzheimer’s disease is linked to increased levels of amyloid beta (Aβ) in the brain, but the mechanisms underlying neuronal dysfunction and neurodegeneration remain enigmatic. Here, we investigate whether organizational characteristics of functional presynaptic vesicle pools, key determinants of information transmission in the central nervous system, are targets for elevated Aβ. Using an optical readout method in cultured hippocampal neurons, we show that acute Aβ42 treatment significantly enlarges the fraction of functional vesicles at individual terminals. We observe the same effect in a chronically elevated Aβ transgenic model (APPSw,Ind) using an ultrastructure-function approach that provides detailed information on nanoscale vesicle pool positioning. Strikingly, elevated Aβ is correlated with excessive accumulation of recycled vesicles near putative endocytic sites, which is consistent with deficits in vesicle retrieval pathways. Using the glutamate reporter, iGluSnFR, we show that there are parallel functional consequences, where ongoing information signaling capacity is constrained. Treatment with levetiracetam, an antiepileptic that dampens synaptic hyperactivity, partially rescues these transmission defects. Our findings implicate organizational and dynamic features of functional vesicle pools as targets in Aβ-driven synaptic impairment, suggesting that interventions to relieve the overloading of vesicle retrieval pathways might have promising therapeutic value.

Dityrosine cross-linking and its potential roles in Alzheimer’s disease

“…Many pieces of evidence have subsequently shown that the oligomeric form of Aβ is the most toxic species, not fibrils, even though a consensus is lacking about the exact structure and composition of these soluble species ( Benilova et al, 2012 ). Accumulated evidence shows that Aβ oligomers disrupt cellular function in cultured cells and animal models ( Lambert et al, 1998 ; Lacor et al, 2007 ; Reddy and Beal, 2008 ; Wu et al, 2010 ; Li et al, 2011 ; Soura et al, 2012 ; Zhang et al, 2014 ; Fuchsberger et al, 2016 ; Marshall et al, 2016 , 2020 ; Selkoe and Hardy, 2016 ; Biasetti et al, 2023 ). In the double-transgenic APP swe -Tau mouse, neuronal loss and activated astrocytes in the entorhinal cortex and the CA1 hippocampal subfield were found to correlate with the burden of Aβ oligomers ( DaRocha-Souto et al, 2011 ).…”

Post-Synapses in the Brain: Role of Dendritic and Spine Structures

“…Several studies, however, have demonstrated that, in patients already showing severe lesions, cognition can be slowly recovered. Such cognitive resilience processes are due to changes in spine density and morphology [ 87 , 88 ]. This possibility has been strengthened by recent demonstration that remodeling of spine structures is a plausible mechanism to protect synapses by cognitive resilience [ 88 , 89 ].…”

Potassium homeostasis during disease progression of Alzheimer’s Disease

“…However, prior to the extensive neurodegeneration, neurons in AD patients and transgenic AD mouse models, express aberrant patterns of cellular and network oscillatory rhythmic activity that may facilitate the cognitive decline associated with AD (3). Some of the suggested underlying mechanisms for the abnormal network activity includes the disruption of synaptic functionality (4) and neuronal hyperexcitability (5) that affects neuronal network circuitry. However, as glial cells are integral players in synaptic function and neuronal circuits, their malfunction can also promote neuronal hyperexcitability and hypersynchrony (6–9).…”