Abstract
Current treatment options for patients with Alzheimer’s disease (AD) are limited at providing symptomatic relief, with no effects on the underlying pathophysiology. Recently, advances in the understanding of the AD pathogenesis highlighted the role of ABeta (Aβ) oligomers particularly interfering with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD). These findings led to the development of potential anti-amyloid therapies, and among them homotaurine, a glycosaminoglycan mimetic designed to interfere with the actions of Aβ early in the cascade of amyloidogenic events, and by its γ-aminobutyric acid type (GABA) A receptor affinity. Recently, we showed that AD patients have impaired LTP-like cortical plasticity, as measured by standard theta burst stimulation protocols applied over the primary motor cortex (M1). Furthermore, AD patients have a weakened short latency afferent inhibition (SLAI), a neurophysiological measure of central cholinergic transmission, which changes reflect the cholinergic dysfunction occurring in the pathology. Here, we aimed at investigating whether homotaurine administration could modulate in vivo measured mechanisms of synaptic plasticity, namely LTP and LTD, and also SLAI in a group of mild cognitive impaired patients. We observed that homotaurine administration did not induce relevant changes of both LTP and LTD recordings, while induced changes of SLAI in our group of patients. We suggest that homotaurine effects are dependent on changes of cortical GABA transmission suggesting a potential role for this compound in ameliorating the cholinergic transmission by modulating the inhibitory cortical activity.
Highlights
Mild cognitive impairment (MCI) is a cognitive status difficult to define
The anti-amyloid properties associated to the GABA profile, make homotaurine a new potential drug for treatment of Alzheimer’s disease (AD) (Caltagirone et al, 2012)
Since most of the pathological changes observed in AD have been shown to start long before cognitive decline appears (Mattsson et al, 2009; Lim et al, 2014), an appropriate treatment strategy would indicate homotaurine for patients with MCI, a condition that potentially reverse to AD
Summary
Mild cognitive impairment (MCI) is a cognitive status difficult to define. It represents the gray area set between the normal and pathologic cognition. The progressive accumulation of these peptides, associated with a reduced clearance, would promote aggregation of Aβ peptides in oligomers and fibrils, species with a powerful toxic effect on neurons responsible for dramatic changes of synaptic plasticity machinery with impaired long-term potentiation (LTP) and prolonged long-term depression (LTD), spine shrinkage and loss, and neuronal degeneration (Shankar et al, 2008; Palop and Mucke, 2010). These changes are supposed to start long before cognitive decline appear, low Aβ levels could be detected in MCI patients.
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