The role of SLC4A4 in vascular dementia

The National Institute of Neurological Disorders and Stroke awarded Baylor College of Medicine $149,766 on September 6, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to investigate the role of the SLC4A4 gene in vascular dementia progression.

The research combines a SLC4A4 conditional knockout mouse model with an established vascular dementia injury model to examine how astrocytic SLC4A4 influences blood-brain barrier integrity, pH regulation, and cognitive function. Preliminary data from the recipient's work indicate that SLC4A4 depletion in astrocytes exacerbates cognitive deficits and alters microglial and astrocyte populations in vascular dementia conditions, while SLC4A4 overexpression after vascular dementia injury reduces glial activation. Bulk RNA sequencing reveals gene enrichment associated with cognitive deficits and neurotransmitter dysfunction in SLC4A4-depleted mice, though underlying mechanisms remain unknown. The project proposes three aims: characterizing SLC4A4 expression in human vascular dementia tissue and the mouse model, investigating mechanism of action, and translating findings to potential therapeutic targets.

Performance occurs in Houston, Texas. The period of performance runs from the award date through January 6, 2029.

Abstract

Vascular dementia (VAD), the second most common subtype of dementia, is a neurological brain disorder in which cognitive deficits are attributed to cerebrovascular pathologies. Cognitive impairment and neuronal dysfunction are two of the major hallmarks of VAD. Throughout disease progression, vascular pathologies change the integrity of the neurovascular unit (NVU), a complex environment of cells that regulate brain homeostasis such as blood-brain barrier (BBB) and PH regulation. Astrocytes are glial cells within the NVU that serve a variety of functions, including the maintenance of the BBB and ION balance. Studies have shown that an astrocyte-enriched gene, SLC4A4, encoding for a sodium-bicarbonate cotransporter, has a role in regulating BBB integrity in both physiological and stroke conditions, as well as participating in PH buffering to mediate neuronal activity. This raises the question of whether astrocytes function in the progression of cellular pathologies and cognitive impairments seen in VAD. To investigate this, i combined our SLC4A4 conditional knockout mouse with an established VAD injury model to recapitulate and study the pathology of this disease. My preliminary data indicate a decrease of mature neuronal cells, elevated cell counts and morphological complexity of microglia, and a reduction of astrocytes, with severe cognitive deficits upon VAD injury in SLC4A4-depleted mice. When astrocytic SLC4A4 is overexpressed after VAD injury, i observed alleviation glial activation. Furthermore, bulk RNA sequencing of SLC4A4-CKO mice post VAD injury highlights an enrichment of genes associated with cognitive deficits and neurotransmitter dysfunction; however, the underlying mechanisms remains unknown. To bridge this knowledge GAP, i propose three aims to investigate the role of astrocytic SLC4A4 in VAD progression. First, i will characterize SLC4A4 expression in human VAD tissue and in my VAD mouse model, additionally, assess cognitive and NVU VAD pathology in SLC4A4-CKO mice after VAD injury. Next, i will explore whether overexpression of astrocytic SLC4A4 rescues detrimental phenotypes in VAD. Finally, i will examine the functional correlation of SLC1A3, a candidate gene upregulated in SLC4A4-CKO mice in human VAD and during VAD in SLC4A4-CKO mice, in SLC4A4-dependent synaptic dysregulation. Additionally, i will test the synaptic and NVU changes upon pharmacological inhibition and overexpression of SLC1A3 in VAD-injured SLC4A4-CKO mice. Altogether, these studies will aid our understanding of the influence of SLC4A4 in VAD, paving the way for the development of essential therapeutic targeted strategies.