- PDGFR-β haploinsufficiency causes pericyte loss, reduced tight junction proteins, basement membrane defects and increased hippocampal BBB permeability.
- These vascular changes associate with elevated DNA damage response and increased p16-positive senescent cells in the hippocampus.
- Resultant hippocampal impairment includes markedly reduced SOX2-positive neural progenitors and DCX-positive immature neurons, indicating impaired neurogenesis and accelerated cellular ageing.
Biochem Biophys Res Commun. 2026 Aug 18;834:154456. doi: 10.1016/j.bbrc.2026.154456. Online ahead of print.
ABSTRACT
BACKGROUND: Platelet-Derived Growth Factor Receptor Beta (PDGFR-β), a key marker of cerebrovascular pericytes, plays a crucial role in regulating pericyte function and maintaining the stability of the blood-brain barrier (BBB). Recent studies suggest that abnormalities in the PDGFR-β signaling pathway may be closely associated with the onset and progression of neurodegenerative diseases. However, the causal relationship and specific mechanisms by which PDGFR-β gene deficiency directly leads to systemic pathological alterations in the hippocampal microenvironment, subsequently causing impaired neurogenesis and cellular senescence, remain unclear.
METHODS: Using PDGFR-β heterozygous knockout (PDGFR-β+/-) mice, we systematically examined pericyte coverage, BBB integrity, cellular senescence markers, and hippocampal neurogenesis.
RESULTS: PDGFR-β ± mice exhibited significant pericyte loss, reduced tight junction proteins, impaired vascular basement membrane, and increased BBB permeability in the hippocampus. These changes were accompanied by elevated DNA damage response, increased p16-positive senescent cells, and markedly reduced numbers of SOX2-positive neural stem/progenitor cells and DCX-positive immature neurons in the hippocampus.
CONCLUSION: Our findings establish that PDGFR-β haploinsufficiency drives pericyte loss and BBB breakdown, leading to hippocampal cellular senescence and impaired neurogenesis. This highlights vascular instability as a key driver of brain aging and positions pericyte dysfunction as a critical link between genetic susceptibility and age-related cognitive decline.
PMID:42632331 | DOI:10.1016/j.bbrc.2026.154456
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