Impairments of neural circuit function in Alzheimer's disease

Abstract

An essential feature of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) peptides in the brain, many years to decades before the onset of overt cognitive symptoms. We suggest that during this very extended early phase of the disease, soluble Aβ oligomers and amyloid plaques alter the function of local neuronal circuits and large-scale networks by disrupting the balance of synaptic excitation and inhibition ( E / I balance) in the brain. The analysis of mouse models of AD revealed that an Aβ-induced change of the E / I balance caused hyperactivity in cortical and hippocampal neurons, a breakdown of slow-wave oscillations, as well as network hypersynchrony. Remarkably, hyperactivity of hippocampal neurons precedes amyloid plaque formation, suggesting that hyperactivity is one of the earliest dysfunctions in the pathophysiological cascade initiated by abnormal Aβ accumulation. Therapeutics that correct the E / I balance in early AD may prevent neuronal dysfunction, widespread cell loss and cognitive impairments associated with later stages of the disease. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

“…feature in AD-like mouse models and in humans with early-stage AD, underlying behavior-relevant local and long-range circuit dysfunctions (14)(15)(16). Our experiments demonstrated that treatment with NB-360 effectively abolished excess neuronal activity in transgenic mice (Fig.…”

Novel Quantitative Analyses of Spontaneous Synaptic Events in Cortical Pyramidal Cells Reveal Subtle Parvalbumin-Expressing Interneuron Dysfunction in a Knock-In Mouse Model of Alzheimer’s Disease

“…Studies have shown that a disrupted E/I balance can cause network dysfunction and various diseases (Fernandez et al, 2007; Kehrer et al, 2008; Gogolla et al, 2009), including AD (Schmitt, 2005; Rissman and Mobley, 2011; Busche and Konnerth, 2016). Therefore, after examining the excitatory and inhibitory currents separately in pyramidal cells, we also wanted to check whether the E/I balance is altered in App NL-F mice.…”

“…The pathologic hallmarks of AD include amyloid β (Aβ) plaques, neurofibrillary tangles (NFTs), and neuronal degeneration (Serrano-Pozo et al, 2011). Meanwhile, neuronal hyperactivity, network hyperexcitability, and spontaneous epileptiform activity have been observed in human amyloid precursor protein (hAPP) transgenic mouse models with high levels of Aβ (Palop et al, 2007, 2011; Busche et al, 2008; Palop and Mucke, 2009; Harris et al, 2010; Roberson et al, 2011; Yan et al, 2012; Busche and Konnerth, 2016). Hypersynchronous network activity, also observed in AD patients (Lam et al, 2017), may further contribute to the emergence of AD symptoms such as cognitive impairment in early stages of the disease (Noebels, 2011; Bakker et al, 2012; Scharfman, 2012).…”

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

“…The topic of amyloidogenesis has been the subject of many scientific endeavors and a great variety of papers have been published, approaching the problem from all possible angles: diagnostics [63][64][65][66], therapeutic [67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] and structural/molecular [82][83][84][85]. Our publication does not, however, discuss amyloidogenesis as such, but rather the molecular processes which lead to the formation of fibrillary aggregates commonly referred to as amyloids.…”