Compensating for synaptic loss in Alzheimer’s disease

Abstract

Confirming that synaptic loss is directly related to cognitive deficit in Alzheimer's disease (AD) has been the focus of many studies. Compensation mechanisms counteract synaptic loss and prevent the catastrophic amnesia induced by synaptic loss via maintaining the activity levels of neural circuits. Here we investigate the interplay between various synaptic degeneration and compensation mechanisms, and abnormal cortical oscillations based on a large-scale network model consisting of 100,000 neurons exhibiting several cortical firing patterns, 8.5 million synapses, short-term plasticity, axonal delays and receptor kinetics. The structure of the model is inspired by the anatomy of the cerebral cortex. The results of the modelling study suggest that cortical oscillations respond differently to compensation mechanisms. Local compensation preserves the baseline activity of theta (5-7 Hz) and alpha (8-12 Hz) oscillations whereas delta (1-4 Hz) and beta (13-30 Hz) oscillations are maintained via global compensation. Applying compensation mechanisms independently shows greater effects than combining both compensation mechanisms in one model and applying them in parallel. Consequently, it can be speculated that enhancing local compensation might recover the neural processes and cognitive functions that are associated with theta and alpha oscillations whereas inducing global compensation might contribute to the repair of neural (cognitive) processes which are associated with delta and beta band activity. Compensation mechanisms may vary across cortical regions and the activation of inappropriate compensation mechanism in a particular region may fail to recover network dynamics and/or induce secondary pathological changes in the network.

Synaptic plasticity at the interface of health and disease: New insights on the role of endoplasmic reticulum intracellular calcium stores

“…On the one hand, it has been proposed that homeostatic synaptic plasticity could counteract the diseaseinduced loss of afferent input to neurons by keeping the activity of the affected neurons within a physiological range. Such a mechanism could be beneficial by maintaining circuit excitability and may retard memory loss in Alzheimer's disease (AD; Small, 2008;Abuhassan et al, 2014). On the other hand it has been also discussed that epilepsy could be a consequence of homeostatic plasticity (Trasande and Ramirez, 2007;Frohlich et al, 2008;Savin et al, 2009).…”

Compensating for thalamocortical synaptic loss in Alzheimer's disease

“…In a recent modeling study we find that the homogeneous increase in the strength of the remaining synapses changes the distribution of firing rates across excitatory neurons (Abuhassan et al, 2013). It stimulates silent excitatory neurons (0 Hz) and increases the fractions of low activity excitatory neurons (1–3 Hz) and active excitatory neurons (4–10 Hz).…”

“…The study builds on the presented cortical models in our previous two studies (Abuhassan et al, 2012, 2013) by including the thalamus, an important subcortical structure involved in language, executive functioning, attention and memory functions (Johnson and Ojemann, 2000; Van der Werf et al, 2003). Such cognitive functions are deteriorated in AD (Van der Werf et al, 2003; Zhao et al, 2012).…”

“…In a previous study (Abuhassan et al, 2013), we described an investigation into three types of compensation mechanisms in a cortical network, namely global (network-based), local (neuronal-based) and combined (local and global) compensation mechanisms. In contrast, this study investigates compensation mechanism from another point of view.…”

Characterization of hippocampal Cajal-Retzius cells during development in a mouse model of Alzheimer′s disease (Tg2576)

“…Because Cajal-Retzius cells and reelin play key roles in the guidance of neuronal migration and maturation, small changes in Cajal-Retzius cell numbers in Tg2576 mice may induce large alterations in neurogenesis, neuronal migration, and neuronal pathfinding. Therefore, dysregulation of neurogenesis, neuronal migration, and neuronal pathfinding may contribute to cognitive impairments in Alzheimer's disease patients[5259]. …”