Citations

Transactive response DNA‐binding protein 43 (TDP‐43) pathological inclusions are found in frontotemporal lobar degeneration (FTLD‐TDP) and Alzheimer's disease (AD‐TDP). While clinically different, TDP‐43 inclusions in FTLD‐TDP and AD can have similar morphological characteristics. However, TDP‐43 colocalizing with tau and forming “apple‐bite” or “flame‐shaped” neuronal cytoplasmic inclusions (NCI) are only found in AD‐TDP. Here, we describe a case with AD and neuritic plaque‐associated TDP‐43. The patient was a 96‐year‐old right‐handed Caucasian woman who had developed a slowly progressive amnestic syndrome compatible with typical AD at age 80. Genetic testing revealed APOE ε3/ε4, GRN r5848 CT, and MAPT H1/H2 genotype. Consistent with the old age at onset and long disease duration, limbic‐predominant AD was found at autopsy, with high hippocampal yet low cortical neurofibrillary tangle (NFT) counts. Hippocampal and amygdala sclerosis were present. Immunohistochemistry for phospho‐TDP‐43 showed NCIs, dystrophic neurites, and rare neuronal intranuclear inclusions consistent with FTLD‐TDP type A, as well as tau NFT‐associated TDP‐43 inclusions. These were frequent in the amygdala, entorhinal cortex, hippocampus, occipitotemporal gyrus, and inferior temporal gyrus but sparse in the mid‐frontal cortex. Additionally, there were TDP‐43‐immunoreactive inclusions forming plaque‐like structures in the molecular layer of the dentate fascia of the hippocampus. The presence of neuritic plaques in the same region was confirmed using thioflavin‐S fluorescent microscopy and immunohistochemistry for phospho‐tau. Double labeling immunofluorescence showed colocalization of TDP‐43 and tau within neuritic plaques. Other pathologies included mild Lewy body pathology predominantly affecting the amygdala and olfactory bulb, aging‐related tau astrogliopathy, and mixed small vessel disease (arteriolosclerosis and amyloid angiopathy) with several cortical microinfarcts. In conclusion, we have identified TDP‐43 colocalizing with tau in neuritic plaques in AD, which expands the association of TDP‐43 and tau in AD beyond NFTs. The clinical correlate of this plaque‐associated TDP‐43 appears to be a slowly progressive amnestic syndrome.

An imbalance in goal-directed and habitual behavioral control is a hallmark of decision-making–related disorders, including addiction. Although external globus pallidus (GPe) is critical for action selection, which harbors enriched astrocytes, the role of GPe astrocytes involved in action-selection strategies remained unknown. Using in vivo calcium signaling with fiber photometry, we found substantially attenuated GPe astrocytic activity during habitual learning compared to goal-directed learning. The support vector machine analysis predicted the behavioral outcomes. Chemogenetic activation of the astrocytes or inhibition of GPe pan-neuronal activities facilitates the transition from habit to goal-directed reward-seeking behavior. Next, we found increased astrocyte-specific GABA (γ-aminobutyric acid) transporter type 3 (GAT3) messenger RNA expression during habit learning. Notably, the pharmacological inhibition of GAT3 occluded astrocyte activation–induced transition from habitual to goal-directed behavior. On the other hand, attentional stimuli shifted the habit to goal-directed behaviors. Our findings suggest that the GPe astrocytes regulate the action selection strategy and behavioral flexibility.