Yun Li

Alzheimer’s disease (AD) is characterized by a progressive cognitive decline and pathological cascade involving amyloid-β (Aβ) plaque, hyperphosphorylated tau (pTau), neuroinflammation, and neurodegeneration. Although anti-amyloid antibody therapies have recently been approved, their clinical benefits remain limited and often accompanied with significant adverse effects. Physical activity has emerged as a promising non-pharmacological intervention for AD, with both aerobic and resistance physical activity showing beneficial effects in preclinical studies. However, the effects of different types of physical activity remain insufficiently understood. In this study, we investigated the effects of a forced treadmill running and ladder climbing physical activity procedure on cognitive behaviors, gliosis, and protein aggregate pathology in aged 3xTg-AD mice. Thirteen to fourteen months old 3xTg-AD mice were subjected to a six-week forced treadmill running and ladder climbing physical activity protocol. Cognitive functions were evaluated using the novel object recognition, Y-maze, and social behavior tests. Hippocampal and cortical tissues were analyzed by immunostaining for Aβ, pTau, Glial Fibrillary Acidic Protein (GFAP), Ionized Calcium-Binding Adapter Molecule 1 (IBA1), and inhibitory neuron markers. Our study demonstrated that the six-week forced treadmill running and ladder climbing physical activity procedure reduced age-associated cognitive declines in spatial working memory, object recognition memory, and sociability in aged 3xTg-AD mice. Such physical activity procedure also reduced Thioflavin S (Thio S) labeled misfolded protein aggregates and reactive gliosis in the cortex and/or hippocampus. Notably, forced treadmill running and ladder climbing physical activity procedure decreased Thio S positive neuropathology within somatostatin-positive interneurons of the hippocampus and cortex, indicating a cell-specific neuroprotective effect. Our results demonstrated that forced treadmill running and ladder climbing physical activity procedure produced significant behavioral and neuropathological benefits in aged 3xTg-AD mice, supporting physical activity as a promising non-pharmacological intervention for modulating gliosis and protein aggregate pathology in aging and AD.

The heat shock protein (HSP) family comprises six sub-families whose members participate in a wide array of cellular processes. This minireview focuses on three specific heat shock proteins: Hsp90aa and Hsp90ab from the Hsp90 sub-family, Hsc70 (Hspa8) from the Hsp70 sub-family, and the Hsp40 co-chaperone sub-family. In neuronal cells, these HSPs play critical roles in maintaining proper synaptic proteostasis. We have summarized current evidence for how these HSPs act independently and collaboratively to maintain synaptic proteostasis. Importantly, emerging data suggests that synaptic disruptions of Hsp90, Hsc70, or their Hsp40 partners not only contribute to hallmarks of neurodegenerative pathology but also contribute to psychiatric conditions such as depression and post-traumatic stress disorder (PTSD). By integrating findings across these two disease categories, we propose that dysfunctional chaperones at the synapse represent a molecular link between neurodegenerative and neuropsychiatric disorders.

As a well-developed branch of mathematics, graph theory provides unique tools to quantifiably assess various properties of complex networks. Applied to brain circuits, network-level analyses can illustrate disruptions to brain organization that yield both mechanistic and diagnostic insights. Previously, graph theory has been used with functional magnetic resonance imaging datasets to quantify connections among different brain regions, readily capturing the macroscopic-scaled differences in brain networks between healthy and Alzheimer’s subjects. Here, we applied graph theory on the microscopic scale, using miniscope-based calcium imaging from the freely behaving wild type (WT) and Shank3 ^fx mice (a mouse model of autism), and compared functional connections among individual neurons in the prefrontal microcircuits during social behavior. We demonstrated that Shank3 ^fx mice displayed reduced neural activity, less-integrated network, and fewer network changes in the prefrontal microcircuits between the presence and absence of social targets. Furthermore, we employed machine learning to test whether graph-theoretic metrics extracted from the prefrontal microcircuits could be predictive of genotype and genotype-associated social behavior difference between Shank3 ^fx and WT mice. Our results indicate a strong link between altered prefrontal microcircuits and social behavior deficits in an autism mouse model, highlighting prefrontal microcircuitry as a potential diagnostic and therapeutic target for autism.

Background: Mislocalization of TAR DNA binding protein 43 kDa (TAPDBP, or TDP-43) is a principle pathological hallmark identified in cases of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As an RNA binding protein, TDP-43 serves in the nuclear compartment to repress nonconserved cryptic exons to ensure the generation of a normal transcriptome. Since nuclear depletion of TDP-43 is frequently observed independent of its cytosolic accumulation, a loss-of-function mechanism has been proposed to contribute to neurodegeneration. Multiple lines of evidence from animal models and human studies support the view that loss of TDP-43 leads to neuron loss, independent of its cytosolic aggregation. However, the underlying pathogenic pathways driven by the loss-of-function mechanism are still poorly defined. Methods: We employed a genetic approach to determine the impact of TDP-43 loss in pyramidal neurons of the prefrontal cortex (PFC). Young adult male homozygous floxed Tdp-43^F/F mice were bilaterally injected into the PFC with mixed viruses containing a Cre virus driven by the CaMKII promoter and a Cre-dependent virus expressing a genetically encoded green fluorescent calcium indicator, GCaMP6f. This approach allowed us to specifically deplete TDP-43 and express GCaMP6f in pyramidal neurons of the PFC. We also bilaterally injected a virus expressing GCaMP6f driven by the CaMKII promoter into the PFC of age-matched male Tdp-43^F/F mice as controls. Using a custom-built miniscope imaging system, we performed repetitive in vivo calcium imaging from freely behaving mice for up to 7 months, to monitor the dynamic changes of calcium activity in PFC pyramidal neurons of TDP-43 depleted and TDP-43 intact mice. Results: By comparing calcium activity in PFC pyramidal neurons between TDP-43 depleted and TDP-43 intact mice, we demonstrated remarkably increased numbers of pyramidal neurons exhibiting hyperactive calcium activity after short-term TDP-43 depletion, followed by rapid activity declines during disease progression. We further demonstrated that long-term TDP-43 depletion was accompanied by a significant reduction in neuron numbers and increased gliosis in the PFC. Conclusions: Our results suggest that TDP-43 loss-of-function drives dynamic changes in neural activity prior to neurodegeneration, highlighting the role of aberrant neural activity and dysfunctional calcium signaling in the pathogenesis of neurodegenerative diseases including ALS and FTD.

Depression is an umbrella term used to describe a mood disorder with a broad spectrum of symptoms including a persistent feeling of sadness, loss of interest, and deficits in social behavior. Epigenetic research bridges the environmental and genetic landscape and has the potential to exponentially improve our understanding of such a complex disorder. Depression is also a sexually dimorphic disorder and variations exist within epigenetic modification sites between sexes. These sex-specific mediators may impact behavioral symptomology and could serve as therapeutic targets for treatments to improve behavioral deficits. This mini review will focus on the social behavior perspective of depression and specifically explore the sexually different epigenetic modifications on depression.