Network abnormalities and interneuron dysfunction in Alzheimer disease

Abstract

The function of neural circuits and networks can be controlled, in part, by modulating the synchrony of their components' activities. Network hypersynchrony and altered oscillatory rhythmic activity may contribute to cognitive abnormalities in Alzheimer disease (AD). In this condition, network activities that support cognition are altered decades before clinical disease onset, and these alterations predict future pathology and brain atrophy. Although the precise causes and pathophysiological consequences of these network alterations remain to be defined, interneuron dysfunction and network abnormalities have emerged as potential mechanisms of cognitive dysfunction in AD and related disorders. Here, we explore the concept that modulating these mechanisms may help to improve brain function in these conditions.

Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer’s Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade

“…The antiepileptic drug levetiracetam improved memory performance in MCI subjects (Bakker et al, 2012, 2015), and, in hAPPJ20 mice, suppressed epileptiform activity and ameliorated memory dysfunction (Sanchez et al, 2012). As shown in AD mice, early-onset hypersynchronous network activity may trigger changes in the hippocampal circuitry, including remodeling of inhibitory interneuron network, NPY ectopic expression, and probably aberrant neurogenesis, leading to progressive deterioration of hippocampal function that culminates in age-dependent cognitive decline (Palop et al, 2007; Palop and Mucke, 2009, 2016; Bezzina et al, 2015). …”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…The gist of the cumulative data is that (1) hallmarks of aging promote amyloidogenic APP processing and Tau pathology, (2) Aβ and Tau accumulations accelerate hallmarks of aging, and (3) there is no common linear pathway to synaptic dysfunction and neuronal death in AD. For indepth information on the roles of different hallmarks of brain aging in AD and related dementias, we refer the reader to the following review articles: oxidative stress (Texel and Mattson, 2011), mitochondrial dysfunction (Mattson et al, 2008; DuBoff et al, 2013), impaired autophagy (Nixon, 2013; Kerr et al, 2017), impaired DNA repair (Madabhushi et al, 2014; Leandro et al, 2015), aberrant neuronal network excitability (Palop and Mucke, 2016; Vossel et al, 2017), impaired adaptive stress response signaling (Stranahan and Mattson, 2012), dysregulated neuronal Ca 2+ homeostasis (Bezprozvanny and Mattson, 2008; Stutzmann and Mattson, 2011), impaired energy metabolism (Dauncey, 2014), neuroinflammation (Heppner et al, 2015), and stem cell deficits (Lazarov et al, 2010). Due to space limitations, in this section we describe one specific example of how oxidative damage, impaired autophagy, Ca 2+ dyshomeostasis, and aberrant neuronal network activity can interact reciprocally with Aβ pathology to cause synaptic dysfunction and neuronal death in AD.…”

Alterations of Coherent Theta and Gamma Network Oscillations as an Early Biomarker of Temporal Lobe Epilepsy and Alzheimer’s Disease

“…Thus, aging is a common and well-established risk factor for epilepsy and AD (Armon et al, 2000; Maguire and Frith, 2003; Amatniek et al, 2006; Bernardi et al, 2010; Born et al, 2014; Chan et al, 2015). Besides, AD may be an important cause of epileptic disorders, as shown in elderly humans (Armon et al, 2000; Bird et al, 2005; Bernardi et al, 2010; Palop and Mucke, 2016) and in animals with AD models (Bezzina et al, 2015; Chan et al, 2015). Patients with AD have a 5- to 10-fold increased risk of the development of seizures or other forms of epileptiform activity (Amatniek et al, 2006).…”