Abstract
Interneurons, key regulators of hippocampal neuronal network excitability and synchronization, are lost in advanced stages of Alzheimer’s disease (AD). Given that network changes occur at early (presymptomatic) stages, we explored whether alterations of interneurons also occur before amyloid-beta (Aβ) accumulation. Numbers of neuropeptide Y (NPY) and parvalbumin (PV) immunoreactive (IR) cells were decreased in the hippocampus of 1 month-old TgCRND8 mouse AD model in a sub-regionally specific manner. The most prominent change observed was a decrease in the number of PV-IR cells that selectively affected CA1/2 and subiculum, with the pyramidal layer (PY) of CA1/2 accounting almost entirely for the reduction in number of hippocampal PV-IR cells. As PV neurons were decreased selectively in CA1/2 and subiculum, and given that they are critically involved in the control of hippocampal theta oscillations, we then assessed intrinsic theta oscillations in these regions after a 4-aminopyridine (4AP) challenge. This revealed increased theta power and population bursts in TgCRND8 mice compared to non-transgenic (nTg) controls, suggesting a hyperexcitability network state. Taken together, our results identify for the first time AD-related alterations in hippocampal interneuron function as early as at 1 month of age. These early functional alterations occurring before amyloid deposition may contribute to cognitive dysfunction in AD.
Highlights
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive loss of cognitive and executive functions
The labeling data obtained with FCA3340 and CT20 indicated that immunoreactivity likely arises from the presence of amyloid precursor protein (APP) and its first cleavage products (CTFs) in the absence of Amyloid beta (Aβ)
Since the observed putative C-terminal fragments (CTF)-IR could arise from different fragments generated along either the amyloidogenic and non-amyloidogenic pathways, we performed a selective C-terminal fragment beta (βCTF) enzyme-linked immunoabsorbent assay (ELISA) to assess whether the CT20-IR could be due to the βCTF
Summary
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive loss of cognitive and executive functions. AD develops over decades, and overt stages are commonly studied, little is known about the mechanisms occurring in the earliest stages (Prince et al, 2014) Understanding these upstream mechanisms is crucial for identifying early diagnostic biomarkers, as well as therapeutic targets that could help modify disease progression more efficiently. The prevailing theory regarding the cause of AD is the amyloid cascade hypothesis, which posits that overproduction of Aβ from amyloid precursor protein (APP) initiates a series of events, including synaptic dysfunction, microglial and astrocytic activation and hyperphosphorylation of tau, which culminates in widespread neuronal death and neurodegeneration (Hardy and Selkoe, 2002). Because βCTF accumulates prior to Aβ (Cavanagh et al, 2013) and because its deleterious effects such as neurodegeneration (Kammesheidt et al, 1992) and synaptic abnormalities (Oster-Granite et al, 1996) resemble those associated with Aβ, AD-related pathological alterations may arise even earlier (i.e., before Aβ accumulation) than initially thought
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