Furthermore there has been a growing appreciation that Aβ and NFTs may synergistically act to disrupt synaptic AMPARs. A large body of work has deepened our knowledge of how these pathological metabolites alter AMPAR dynamics to undermine synaptic function. Together with Aβ, NFTs is considered a hallmark of AD but tangles can be found in different neurodegenerative diseases known with the general name of tauopathies. NFTs are aggregates of hyperphosphorylated tau, a protein essential for microtubule assembly ( Cleveland et al., 1977 Harada et al., 1994) whose aberrant conformation has been proposed to induce neurotoxicity. Aβ is a secreted proteolytic derivative of the amyloid precursor protein (APP) which has been linked to early deficits in AD pathogenesis ( Lambert et al., 1998 Lesné et al., 2006). Consistently, one of the earliest biological manifestations of AD dementia is reduced synaptic AMPARs and synaptic plasticity impairments ( Walsh et al., 2002 Shankar et al., 2008 Li et al., 2009 reviewed in Burke and Barnes, 2006 Guntupalli et al., 2016).Īt the molecular level, AD is characterized by the presence of two pathological metabolites: plaques formed by oligomeric clusters of amyloid-β (Aβ) and neurofibrillar tau tangles (NFTs). Over the last two decades researchers have exposed subtle differences in synaptic structure and function at early stages of AD in accord with the notion that subcellular reorganization precedes actual neuronal loss ( Coleman and Flood, 1987 Brown et al., 1998 Scheff et al., 2006 Shankar et al., 2007). alone, AD affects more than 5 million people with an annual cost of over 200 billion 1. Significant advances over the last decades have contributed to our understanding of the processes involved in AMPAR dynamics at synapses, nonetheless how these mechanisms regulate normal synaptic transmission and plasticity and how they go awry during natural aging and neurodegeneration remain unknown.Įlucidating the underlying mechanisms of brain function and decline is especially relevant in today’s society since an increasingly aged population faces higher risks of developing neurodegenerative diseases such as Alzheimer’s disease (AD).
Arguably, one of the most important functions of AMPAR dynamics might be to underlie several forms of synaptic plasticity which has been proposed to act as a subcellular correlate of learning and memory (recently reviewed in Huganir and Nicoll, 2013 Nicoll, 2017). Because of their crucial role in regulating brain function, AMPARs are under tight regulatory processes that control their biosynthesis, membrane trafficking, degradation and various post-translational modifications ( Anggono and Huganir, 2012 Lu and Roche, 2012). The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are glutamate-gated channels that mediate most fast excitatory transmission in the central nervous system (CNS). As a particularly well-studied example of AMPAR dysfunction in pathological aging I focus in Alzheimer’s disease (AD) with special emphasis in how the production of neurofibrillary tangles (NFTs) and amyloid-β plaques may contribute to disruption in AMPAR function. In this review, I provide a brief overview of the molecular mechanisms involved in AMPAR trafficking highlighting what is currently known about how these processes change with age and disease. Understanding the mechanisms that govern AMPAR signaling during natural and pathological cognitive decline will guide the efforts to develop most effective ways to tackle neurodegenerative diseases which are one of the primary burdens afflicting an increasingly aging population. In turn dysregulation of AMPARs can be linked to most neurological and neurodegenerative disorders. Accumulating evidence suggests that the precise regulatory mechanisms involved in orchestrating AMPAR trafficking are challenged in the aging brain. Because of the importance of their function, AMPAR dynamics, activity and subunit composition undergo a tight regulation which begins as early as prenatal development and continues through adulthood. Α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) enable most excitatory transmission in the brain and are crucial for mediating basal synaptic strength and plasticity. Instituto de Neurociencias CSIC-UMH, San Juan de Alicante, Spain.
0 kommentar(er)
