Neuroscientist. 2021 Sep 2:10738584211040786. doi: 10.1177/10738584211040786. Online ahead of print.
As resident immune cells of the brain, microglia serve pivotal roles in regulating neuronal function under both physiological and pathological conditions, including aging and the most prevalent neurodegenerative disease, Alzheimer's disease (AD). Instructed by neurons, microglia regulate synaptic function and guard brain homeostasis throughout life. Dysregulation of microglial function, however, can lead to dire consequences, including aggravated cognitive decline during aging and exacerbated neuropathology in diseases. The triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial function. Loss-of-function variants of TREM2 are associated with an increased risk of AD. TREM2 orchestrates the switch of microglial transcriptome programming that modulates microglial chemotaxis, phagocytosis, and inflammatory responses, as well as microglial regulation of synaptic function in health and disease. Intriguingly, the outcome of microglial/TREM2 function is influenced by age and the context of neuropathology. This review summarizes the rapidly growing research on TREM2 under physiological conditions and in AD, particularly highlighting the impact of TREM2 on neuronal function.
Protein farnesylation is upregulated in Alzheimer's human brains and neuron-specific suppression of farnesyltransferase mitigates pathogenic processes in Alzheimer's model mice
Acta Neuropathol Commun. 2021 Jul 27;9(1):129. doi: 10.1186/s40478-021-01231-5.
The pathogenic mechanisms underlying the development of Alzheimer's disease (AD) remain elusive and to date there are no effective prevention or treatment for AD. Farnesyltransferase (FT) catalyzes a key posttranslational modification process called farnesylation, in which the isoprenoid farnesyl pyrophosphate is attached to target proteins, facilitating their membrane localization and their interactions with downstream effectors. Farnesylated proteins, including the Ras superfamily of small GTPases, are involved in regulating diverse physiological and pathological processes. Emerging evidence suggests that isoprenoids and farnesylated proteins may play an important role in the pathogenesis of AD. However, the dynamics of FT and protein farnesylation in human brains and the specific role of neuronal FT in the pathogenic progression of AD are not known. Here, using postmortem brain tissue from individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), or Alzheimer's dementia, we found that the levels of FT and membrane-associated H-Ras, an exclusively farnesylated protein, and its downstream effector ERK were markedly increased in AD and MCI compared with NCI. To elucidate the specific role of neuronal FT in AD pathogenesis, we generated the transgenic AD model APP/PS1 mice with forebrain neuron-specific FT knockout, followed by a battery of behavioral assessments, biochemical assays, and unbiased transcriptomic analysis. Our results showed that the neuronal FT deletion mitigates memory impairment and amyloid neuropathology in APP/PS1 mice through suppressing amyloid generation and reversing the pathogenic hyperactivation of mTORC1 signaling. These findings suggest that aberrant upregulation of protein farnesylation is an early driving force in the pathogenic cascade of AD and that targeting FT or its downstream signaling pathways presents a viable therapeutic strategy against AD.
Mu Opioid Receptor (Oprm1) Copy Number Influences Nucleus Accumbens Microcircuitry and Reciprocal Social Behaviors
J Neurosci. 2021 Jul 22:JN-RM-2440-20. doi: 10.1523/JNEUROSCI.2440-20.2021. Online ahead of print.
The mu opioid receptor regulates reward derived from both drug use and natural experiences, including social interaction, through actions in the nucleus accumbens. Here, we studied nucleus accumbens microcircuitry and social behavior in male and female mice with heterozygous genetic knockout of the mu opioid receptor (Oprm1+/-). This genetic condition models the partial reduction of mu opioid receptor signaling reported in several neuropsychiatric disorders. We first analyzed inhibitory synapses in the nucleus accumbens, using methods that differentiate between medium spiny neurons (MSNs) expressing the D1 or D2 dopamine receptor. Inhibitory synaptic transmission was increased in D2-MSNs of male mutants, but not female mutants, while the expression of gephyrin mRNA and density of inhibitory synaptic puncta at the cell body of D2-MSNs was increased in mutants of both sexes. Some of these changes were more robust in Oprm1+/- mutants than Oprm1-/- mutants, demonstrating that partial reductions of mu opioid signaling can have large effects. At the behavioral level, social conditioned place preference and reciprocal social interaction were diminished in Oprm1+/- and Oprm1-/- mutants of both sexes. Interaction with Oprm1 mutants also altered the social behavior of wild-type test partners. We corroborated this latter result using a social preference task, in which wild-type mice preferred interactions with another typical mouse over Oprm1 mutants. Surprisingly, Oprm1-/- mice preferred interactions with other Oprm1-/- mutants, even though these interactions did not produce a conditioned place preference. Our results support a role for partial dysregulation of mu opioid signaling in social deficits associated with neuropsychiatric conditions.SIGNIFICANCE STATEMENTActivation of the mu opioid receptor plays a key role in the expression of normal social behaviors. In this study, we examined brain function and social behavior of female and male mice, with either partial or complete genetic deletion of mu opioid receptor expression. We observed abnormal social behavior following both genetic manipulations, as well as changes in the structure and function of synaptic input to a specific population of neurons in the nucleus accumbens, which is an important brain region for social behavior. Synaptic changes were most robust when mu opioid receptor expression was only partially lost, indicating that small reductions in mu opioid receptor signaling can have a large impact on brain function and behavior.