Synaptic Dysfunction in Alzheimer’s Disease

Abstract

Generation of amyloid peptide (Aβ) is at the beginning of a cascade that leads to Alzheimer's disease (AD). Amyloid precursor protein (APP), as well as β- and γ-secretases, is the principal player involved in Aβ production, while α-secretase cleavage on APP prevents Aβ deposition. Recent studies suggested that soluble assembly states of Aβ peptides can cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Therefore, current research investigates the relative importance of these various soluble Aβ assemblies in causing synaptic dysfunction and cognitive deficits. Several Aβ oligomers targets and cellular mechanisms responsible of Aβ-induced synaptic failure have been identified. The first and most important mechanism impugns a toxic gain of function for Aβ which results due to self-association and attainment of new structures capable of novel interactions that lead to impaired plasticity. Other scenarios predicate that Aβ has a normal physiological role. On the one hand, insufficient Aβ could lead to a loss of normal function, whereas excess Aβ may precipitate dysfunction. How this occurs and which the main target/s is/are for the synaptic action of Aβ remains to be fully understood and would certainly represent one of the main challenges to future AD research.

Bushen Huoxue decoction improves cognitive decline in rats with cerebral hypoperfusion

“…Synapse formation and plasticity are necessary for memory recall and consolidation. Previous studies have revealed that synapse loss is associated with cognitive impairment observed in various cognitive dysfunction models, including AD (24,25), middle cerebral artery occlusion (26) and 2VO (27). In the present study, BHD treatment evidently alleviated the synaptic loss induced by cerebral hypoperfusion.…”

Notoginsenoside R1 increases neuronal excitability and ameliorates synaptic and memory dysfunction following amyloid elevation

“…The neurodegeneration observed in AD has been associated with progressive decrease in neuronal activity and synaptic dismantling91039. Modulation of intrinsic properties of individual neurons represents a potential strategy for preventing and/or halting AD progression.…”

A Stem Cell Model of the Motor Circuit Uncouples Motor Neuron Death from Hyperexcitability Induced by SMN Deficiency

“…In recent years, increasing attention has been given to the possibility that synaptic dysfunction within neural networks is an early, initiating event of disease pathogenesis possibly leading to neuronal death (Caviness, 2014; Li et al, 2003; Marcello et al, 2012; Palop and Mucke, 2010). For instance, alterations of basal ganglia circuitry that lead to deficits in motor control and cognitive processes precede loss of substantia nigra neurons in PD (Meredith and Kang, 2006; Muller et al, 2013) and striatal spiny neurons in HD (Mazarakis et al, 2005; Milnerwood and Raymond, 2007; Usdin et al, 1999), respectively.…”