Date of Degree
John H. Martin
Laboratory and Basic Science Research | Molecular and Cellular Neuroscience | Nervous System Diseases
Neurodegeneration, Aging, Protein, Signaling Pathways, Alzheimer's Disease
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with complex underlying pathogenic mechanisms. Epidemiological studies have forecasted that in the next 3 decades, the number of AD cases will rise to epidemic proportions with enormous medical, emotional and financial burdens impacting individuals affected and society. Among many risk factors for AD, advancing age is clearly essential and necessary. Revelation of molecular changes in synaptic activities leading to the prodromal, mild cognitive impairment (MCI) stage may help illuminate the course of pathogenic progression and its cause-effect relationship with various targets thereby enabling target-driven disease-modifying therapeutic agents for AD.
Activity-regulated cytoskeleton-associated (Arc) protein is a prominent regulator of synaptic plasticity and homeostasis that localizes exclusively in postsynaptic regions of the excitatory systems in the brain. Arc is involved in AMPA receptor endocytosis in LTD and late phase LTP consolidation at the dendritic fields. NMDA receptor activation increases Arc expression to facilitate synaptic activities and promote remodeling of dendritic spines. AD pathologies can be found in brains of cognitively normal elderly individuals. Together with the fact that synaptic activity is altered during aging and markedly deteriorated in AD, we therefore hypothesize that altered basal and activity-driven Arc expression contribute to deleterious synaptic changes at old age and in AD. The altered Arc contributes to synaptopathy in AD through its interactions at the postsynaptic density and dendritic spine. However, the mechanisms responsible for Arc alteration during normal aging and in AD are currently not clear.
In these studies, we systemically investigate changes in Arc protein levels under basal and stimulation conditions in hippocampal formation (HF) and prefrontal cortex (PFC) from wild-type (WT) and 3x transgenic (Tg) AD mice at varying ages. The results derived from WT and 3xTg AD mice show Arc protein levels increase along with advancing age and in AD under non-stimulated basal condition. More importantly, Arc expression is increased in response to NMDAR and insulin receptor stimulation and these stimulation-elicited Arc increases are dramatically attenuated in AD. We present evidence to show Arc is regulated by phosphorylation on the serine and tyrosine residues and this post-translational modification process is driven by receptor stimulation. Arc is also sensitive to oxidative damage as indicated by elevation of nitrated Arc levels in aged WT and 3 x Tg AD mice. We reveal that Arc is associated with PSD-95/NMDAR and filamin A (FLNA) signaling pathways. Further, we identify protein kinase C (PKC) and Src in the PSD-95/NMDAR complexes as well as JAK2 and PAK1 in the FLNA signaling cascade as the kinases that phosphorylate Arc following activation of the NMDARs and insulin receptor, respectively. Most importantly, we observed a reduced association of Arc with NMDARs accompanied by increased Arc linkage to FLNA during normal aging and in AD.
The relevancy of the findings in mouse AD models is affirmed by examining the postmortem human HF from age-, gender- and postmortem interval-matched sets of cognitively normal controls, subjects with mild cognitive impairment (MCI) with or without AD pathology (MCI-AD and MCI-SNAP, respectively) and AD cases. Arc protein levels are higher in MCI-SNAP and AD under the non-stimulated conditions. Similar to the observation made in mouse brain, Arc expression is increased by exposure to NMDA/glycine (NMDAR), PNU282987 (α7 nicotinic receptor), insulin (IR) and BDNF (TrkB) in human HF slices from non-demented controls. The receptor stimulation induced Arc expression is universally and markedly reduced in MCI-AD and AD as well as in MCI-SNAP although with lesser extent. Oxidative damage to Arc is evidenced in MCI-AD and AD but not in MCI-SNAP. Arc is predominantly associated with PSD-95/NMDARs in control and MCI-SNAP cases but linked to FLNA in MCI-AD and AD.
In summary, the data presented indicate for the first time that phosphorylation of Arc mediated by kinases in its associated NMDAR and FLNA is a regulatory mechanism for Arc under physiological conditions. More importantly, defected activity-driven Arc expression is observed prevalently in diseases with cognitive impairment. The reduced activity-induced Arc expression can occur with or without elevated Arc protein levels and the altered connections with PSD-95/NMDAR and FLNA signaling complexes. The data derived from this study indicate that reduced activity-driven Arc expression and altered Arc connections occur early in the course of synaptopathy and are integral parts of AD pathologies. Our data suggest that restoring activity-driven Arc expression may rescue synaptic dysfunction and thereby improve cognitive function in diseases with cognitive impairments such as Alzheimer’s disease.
Khan, Amber, "The Master Synaptic Regulator: Activity Regulated Cytoskeleton Associated Protein, Arc, in Normal Aging and Diseases with Cognitive Impairment" (2019). CUNY Academic Works.