Corticothalamic network dysfunction and Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disease that is characterized by progressive cognitive decline and a prominent loss of hippocampal-dependent memory. Therefore, much focus has been placed on understanding the function and dysfunction of the hippocampus in AD. However, AD is also accompanied by a number of other debilitating cognitive and behavioral alterations including deficits in attention, cognitive processing, and sleep maintenance. The underlying mechanisms that give rise to impairments in such diverse behavioral domains are unknown, and identifying them would shed insight into the multifactorial nature of AD as well as reveal potential new therapeutic targets to improve overall function in AD. We present here several lines of evidence that suggest that dysregulation of the corticothalamic network may be a common denominator that contributes to the diverse cognitive and behavioral alterations in AD. First, we will review the mechanisms by which this network regulates processes that include attention, cognitive processing, learning and memory, and sleep maintenance. Then we will review how these behavioral and cognitive domains are altered in AD. We will also discuss how dysregulation of tightly regulated activity in the corticothalamic network can give rise to non-convulsive seizures and other forms of epileptiform activity that have also been documented in both AD patients and transgenic mouse models of AD. In summary, the corticothalamic network has the potential to be a master regulator of diverse cognitive and behavioral domains that are affected in AD.

Accelerated Aging Characterizes the Early Stage of Alzheimer’s Disease

“…It should be noted that, in addition to the reduction of Ca 2+ transients, PS2 mutations linked to FAD-also reduce ATP levels, compromising the functionality of mitochondria as well as the redox state [ 82 , 90 , 91 ], while toxic Aβ oligomers can cause further metabolic and Ca 2+ dysregulation [ 92 , 93 ]. During slow-wave-sleep, synchronous transitions to DOWN-states are also actively controlled by thalamic sensory inputs via the activation of inhibitory interneurons acting on metabotropic GABA-B receptors [ 94 ], a network known to be altered in AD [ 95 , 96 ]. An important role in UP- and DOWN-state transition is also played by the inward rectifying K + channels (GIRK) dependent on G proteins, in particular those linked to GABA-B receptors at the hippocampal level, as shown in mouse AD models [ 97 ].…”

Restoring activity in the thalamic reticular nucleus improves sleep architecture and reduces Aβ accumulation in mice

“…S3). Even subtle changes in TRN activity have been found to have profound consequences for brain function, including effects on attention, sleep maintenance and SWS, hippocampal function, and cognitive domains affected in AD ( 9 , 30 , 38 , 45 , 46 , 66 – 68 ). We therefore hypothesized that the reduced activity of the TRN that we identified could be a causal mechanism driving both sleep fragmentation and reduction in SWS in the APP mice used in our studies and in other transgenic lines of APP mice with high concentrations of Aβ.…”

Alpha peak frequency is linked to episodic memory impairment in pathological aging

“…Furthermore, neurofibrillary tangle deposits were also found in the thalamus at the same Braak stage as those found in the hippocampal region (Braak and Braak, 1991). Still, it is unclear if these thalamic abnormalities are primary related to AD pathology or secondary to cortico-thalamic/hippocampo-thalamic denervation due to neuronal loss (Abuhassan et al, 2014;Aggleton et al, 2016;Jagirdar and Chin, 2020).…”