α-Melanocyte Stimulating Hormone Prevents GABAergic Neuronal Loss and Improves Cognitive Function in Alzheimer's Disease

Abstract

In Alzheimer's disease (AD), appropriate excitatory-inhibitory balance required for memory formation is impaired. Our objective was to elucidate deficits in the inhibitory GABAergic system in the TgCRND8 mouse model of AD to establish a link between GABAergic dysfunction and cognitive function. We sought to determine whether the neuroprotective peptide ␣-melanocyte stimulating hormone (␣-MSH) attenuates GABAergic loss and thus improves cognition. TgCRND8 mice with established ␤-amyloid peptide pathology and nontransgenic littermates were treated with either ␣-MSH or vehicle via daily intraperitoneal injections for 28 d. TgCRND8 mice exhibited spatial memory deficits and altered anxiety that were rescued after ␣-MSH treatment. The expression of GABAergic marker glutamic acid decarboxylase 67 (GAD67) and the number of GABAergic GAD67ϩ interneurons expressing neuropeptide Y and somatostatin are reduced in the hippocampus in vehicle-treated TgCRND8 mice. In the septohippocampal pathway, GABAergic deficits are observed before cholinergic deficits, suggesting that GABAergic loss may underlie behavior deficits in vehicle-treated TgCRND8 mice. ␣-MSH preserves GAD67 expression and prevents loss of the somatostatin-expressing subtype of GABAergic GAD67ϩ inhibitory interneurons. Without decreasing ␤-amyloid peptide load in the brain, ␣-MSH improves spatial memory in TgCRND8 mice and prevents alterations in anxiety. ␣-MSH modulated the excitatory-inhibitory balance in the brain by restoring GABAergic inhibition and, as a result, improved cognition in TgCRND8 mice.

Early‐stage attenuation of phase‐amplitude coupling in the hippocampus and medial prefrontal cortex in a transgenic rat model of Alzheimer's disease

“…Although the expression of GABA A receptor subunits a1, a5, and d was not different between the two cohorts, the expression levels of a1 and a5 subunits in the hippocampus are a poor predictor of the severity of human AD neuropathology (Rissman et al 2003). Further, we found fewer cells expressing the extra synaptic GAD67 protein in the CA1 (and showed a trend in the CA3) region of the transgenic cohort at this time point, in line with the findings in the TgCRND8 mouse model (Krantic et al 2012;Ma and McLaurin 2014). The differential localization suggests that GAD65 synthesizes GABA for neurotransmission, whereas GAD67-mediated production is addressed to neuronal activity unrelated to neurotransmission, such as synaptogenesis and protection from neural injury (Pinal and Tobin 1998).…”

“…Further, we found fewer cells expressing the extra synaptic GAD67 protein in the CA1 (and showed a trend in the CA3) region of the transgenic cohort at this time point, in line with the findings in the TgCRND8 mouse model (Krantic et al . ; Ma and McLaurin ). The differential localization suggests that GAD65 synthesizes GABA for neurotransmission, whereas GAD67‐mediated production is addressed to neuronal activity unrelated to neurotransmission, such as synaptogenesis and protection from neural injury (Pinal and Tobin ).…”

Major amyloid-β–degrading enzymes, endothelin-converting enzyme-2 and neprilysin, are expressed by distinct populations of GABAergic interneurons in hippocampus and neocortex

“…In AD, there is a clear loss of SOM innervation (reviewed in (Martel, et al, 2012) and several studies with APP transgenic mice support that SOM+ cells may be highly vulnerable to pathological Aβ accumulation (Albuquerque, et al, 2015,Ma and McLaurin, 2014,Perez-Cruz, et al, 2011,Ramos, et al, 2006). The sensitivity of these specific interneurons to AD pathology may relate to their putatively high capacity for intracellular Aβ metabolism via expression of ECE-2.…”

A Comparative Study Evaluating the Impact of Physical Exercise on Disease Progression in a Mouse Model of Alzheimer’s Disease

“…used for testing reference and spatial working memory in mice. Here, we used the Y-maze task, which has been validated by our group and others in TgCRND8 mice [24,29,30]. In comparison to the Morris water maze, the Y-maze is less stressful and requires minimal training, thereby minimizing potential confounds of stress hormones and the learning process on outcome measures [31][32][33][34].…”