Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease

Abstract

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD), increasing risk and decreasing age of disease onset. Many studies have demonstrated the detrimental effects of apoE4 in varying cellular contexts. However, the underlying mechanisms explaining how apoE4 leads to cognitive decline are not fully understood. Recently, the combination of human induced pluripotent stem cell (hiPSC) modeling of neurological diseases in vitro and electrophysiological studies in vivo have begun to unravel the intersection between apoE4, neuronal subtype dysfunction or loss, subsequent network deficits, and eventual cognitive decline. In this review, we provide an overview of the literature describing apoE4’s detrimental effects in the central nervous system (CNS), specifically focusing on its contribution to neuronal subtype dysfunction or loss. We focus on γ-aminobutyric acid (GABA)-expressing interneurons in the hippocampus, which are selectively vulnerable to apoE4-mediated neurotoxicity. Additionally, we discuss the importance of the GABAergic inhibitory network to proper cognitive function and how dysfunction of this network manifests in AD. Finally, we examine how apoE4-mediated GABAergic interneuron loss can lead to inhibitory network deficits and how this deficit results in cognitive decline. We propose the following working model: Aging and/or stress induces neuronal expression of apoE. GABAergic interneurons are selectively vulnerable to intracellularly produced apoE4, through a tau dependent mechanism, which leads to their dysfunction and eventual death. In turn, GABAergic interneuron loss causes hyperexcitability and dysregulation of neural networks in the hippocampus and cortex. This dysfunction results in learning, memory, and other cognitive deficits that are the central features of AD.

Friend, Foe or Both? Immune Activity in Alzheimer’s Disease

“…A notable example is the Apoliprotein E (APOE) gene. APOE has three alleles (e2, e3, e4) accounting for proteins that differ by only one or two amino acids Najm et al, 2019). A single copy of APOE4 increases risk of developing AD by 4-fold, and individuals homozygous for APOE4 have an approximately 12-fold increased risk of AD (Bu, 2009).…”

The relationship between physical activity, apolipoprotein E ε4 carriage, and brain health

“…It is believed that the flow of information between different brain regions is sustained by synchronous changes in the frequency, pattern, or strength of their oscillatory activity [12]. Early loss of inhibitory neurons in preclinical AD leads to a state of increased hyperexcitability and hypersynchrony [13][14][15], which has been found to augment amyloid release and produce neurotoxic effects [16,17]. We hypothesize that PA exerts a neuroprotective effect that will be associated with reduced network synchrony in both groups, in opposition to the state of synaptic hyperexcitability that characterizes preclinical and prodromal AD [18][19][20][21][22].…”

The relationship between physical activity, apolipoprotein E ε4 carriage and brain health

“…A closer look at these individuals' brain microstructure provides a plausible explanation for these chronological changes. At the very early silent stages of AD pathology, inhibitory neurons are lost, mainly in middle temporal regions (13,14). Such loss of inhibitory synapses leads to a state of brain hyperexcitability and hypersynchrony, which can be tracked through MEG (15).…”

“…Artifact-free data were segmented in 4 seconds epochs. Then MEG time series were filtered into delta (2-4Hz), theta (4-8Hz), alpha (8-12Hz) and beta (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). This procedure has been reported in detailed in (22).…”

“…It is believed that the flow of information between different brain regions is sustained by synchronous changes in the frequency, pattern or strength of their oscillatory activity (12). Early loss of inhibitory neurons in preclinical AD leads to a state of increased hyperexcitability and hypersynchrony (13)(14)(15), which has been found to augment amyloid release and produce neurotoxic effects (16,17). We hypothesize that PA exerts a neuroprotective effect that will be associated with reduced network synchrony in both groups, in opposition to the state of synaptic hyperexcitability that characterizes preclinical and prodromal AD (18)(19)(20)(21)(22).…”