Major Histocompatibility Complex class I proteins are critical for maintaining neuronal structural complexity in the aging brain

Abstract

Major histocompatibility complex class I (MHCI) proteins have been implicated in neuronal function through the modulation of neuritogenesis, synaptogenesis, synaptic plasticity, and memory consolidation during development. However, the involvement of MHCI in the aged brain is unclear. Here we demonstrate that MHCI deficiency results in significant dendritic atrophy along with an increase in thin dendritic spines and a reduction in stubby spines in the hippocampus of aged (12 month old) mice. Ultrastructural analyses revealed a decrease in spine head diameter and post synaptic density (PSD) area, as well as an increase in overall synapse density, and non-perforated, small spines. Interestingly, we found that the changes in synapse density and morphology appear relatively late (after the age of 6 months). Finally, we found a significant age dependent increase in the levels of the glutamate receptor, GluN2B in aged MHCI knockout mice, with no change in GluA2/3, VGluT1, PSD95 or synaptophysin. These results indicate that MHCI may be also be involved in maintaining brain integrity at post-developmental stages notably in the modulation of neuronal and spine morphology and synaptic function during non-pathological aging which could have significant implications for cognitive function.

Serum β2-Microglobulin Is Closely Associated With the Recurrence Risk and 3-Month Outcome of Acute Ischemic Stroke

“…This result suggests that β2M is closely related to central nervous system inflammation. Recently, the impact of MHC I of the development of the nervous system has attracted researchers' attention, as MHC I plays an important role in regulating axon growth and cortical connections (36). Furthermore, TNF-α and γ-interferon can promote the expression of MHC I and β2M in the central nervous system (37).…”

Astroglial major histocompatibility complex class I following immune activation leads to behavioral and neuropathological changes

“…The expression of MHCI is essential for N‐methyl‐ d ‐aspartic acid (NMDA) receptor‐ and hippocampus‐dependent memory, and MHCI KO (β2m–/– TAP–/–) mice show dysfunctions in social interaction and object recognition (Nelson et al, ). The genetic manipulation of MHCI molecules leads to changes in α‐amino‐2,3‐dihydro‐5‐methyl‐3‐oxo‐4‐isoxazolepropanoic acid and NMDA receptor expression, resulting in impairments in learning and memory (Fourgeaud et al, ; Lazarczyk et al, ). In addition, MHCI negatively regulates the cortical excitation and inhibition balance (Elmer et al, ; Glynn et al, ; Washburn et al, ).…”

Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

“…Physiologically, immune-related receptors such as MHC-I, TNFR1, and IL-1R participate in LTP and modulate learning and memory formation [ 114 ]. For example, neurons from MHC-I-knockout mice show increased synaptic plasticity, excitability, and LTP [ 138 ], which is increased in 12-month old mice [ 139 ], likely exerting this effect via modification of NMDAR and α-amino-3hydorxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function and trafficking [ 140 ]. It has recently been shown that IL-1β directly suppresses hippocampal plasticity via neuron-specific mechanisms [ 141 ] and that increased pro-inflammatory IL-1 accessory protein signaling, specifically at the synapse, underlies the augmented vulnerability to IL-1β-mediated cognitive impairment that occurs with age [ 142 ].…”