Amyloid Beta-Protein and Neural Network Dysfunction

Abstract

Understanding the neural mechanisms underlying brain dysfunction induced by amyloid beta-protein (Aβ) represents one of the major challenges for Alzheimer's disease (AD) research. The most evident symptom of AD is a severe decline in cognition. Cognitive processes, as any other brain function, arise from the activity of specific cell assemblies of interconnected neurons that generate neural network dynamics based on their intrinsic and synaptic properties. Thus, the origin of Aβ-induced cognitive dysfunction, and possibly AD-related cognitive decline, must be found in specific alterations in properties of these cells and their consequences in neural network dynamics. The well-known relationship between AD and alterations in the activity of several neural networks is reflected in the slowing of the electroencephalographic (EEG) activity. Some features of the EEG slowing observed in AD, such as the diminished generation of different network oscillations, can be induced in vivo and in vitro upon Aβ application or by Aβ overproduction in transgenic models. This experimental approach offers the possibility to study the mechanisms involved in cognitive dysfunction produced by Aβ. This type of research may yield not only basic knowledge of neural network dysfunction associated with AD, but also novel options to treat this modern epidemic.

Amyloid β Peptide-Induced Changes in Prefrontal Cortex Activity and Its Response to Hippocampal Input

“…Inhibitory neurons and synapses seem to be more sensitive to the effects of A β [17, 54], which might explain why A β had a major effect on hippocampal input to the PFC when tested at high-frequency stimulation. In fact, this finding is consistent with the observation that fast oscillatory activity, which relies heavily on inhibitory networks [54, 55], is more sensitive to the effects of A β [35, 44, 45, 54] compared to slow oscillatory activity. Moreover, fast oscillatory activity is more disrupted both in AD patients [56, 57] and in AD animal models [54, 58, 59].…”

Amyloid Beta Peptides Differentially Affect Hippocampal Theta RhythmsIn Vitro

“…Interestingly, AD patients show alterations in theta rhythm activity [5, 44, 45]. Some reports indicate that cognitive dysfunction correlates with an increase of resting theta rhythm [5, 8, 44, 45], but other studies show a reduction of cognitive-induced theta rhythm [45]. Similar findings have been observed in transgenic mice that overproduce A β and exhibit AD-like symptoms [8, 46–50].…”

“…Early deterioration of hippocampal function, likely induced by soluble A β , contributes to the initial memory deficits observed in AD patients [4–8]. Interestingly, A β encompasses several peptide species which differ in their length, solubility, biological activity, toxicity, and aggregation propensity [3, 4, 9].…”

“…Normal hippocampal function is strongly dependent on an oscillatory activity called theta rhythm [35–38] which, in lower mammals, includes oscillations ranging from 3 to 12 Hz [35–38]. Hippocampal theta rhythm participates in memory consolidation during REM sleep, in synaptic plasticity, in neural coding of place, and in spatial memory [8, 37, 39–43]. Interestingly, AD patients show alterations in theta rhythm activity [5, 44, 45].…”

“…Some reports indicate that cognitive dysfunction correlates with an increase of resting theta rhythm [5, 8, 44, 45], but other studies show a reduction of cognitive-induced theta rhythm [45]. Similar findings have been observed in transgenic mice that overproduce A β and exhibit AD-like symptoms [8, 46–50]. The complex relationship between AD pathology and theta rhythms can be explained by the theta rhythm heterogeneity that exists both in humans and in mice [51, 52].…”