Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment.

White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.

Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment.

Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the neuro-glial-vascular unit and accumulation of amyloid-ß (Aß) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aß removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aß. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning acquisition and cognitive flexibility. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Our findings show that BCAS influences VCI and that this is paralleled by impaired glymphatic drainage and reduced vascular pulsation. We propose that these additional targets need to be considered when treating VCI.

Cortical tau load is associated with white matter hyperintensities.

INTRODUCTION: Cerebral white matter lesions (WML), visualized as white matter hyperintensities (WMH) on T2-weighted MRI, encompass structural damage and loss of integrity of the cerebral white matter (WM) and are commonly assumed to be associated with small vessel disease (SVD). However, it has been suggested that WM damage may also be the result of degenerative axonal loss that is secondary to cortical Alzheimer's disease (AD) pathologies i.e., hyperphosphorylated tau (HPτ) and amyloid-beta (Aß). Here we investigate the influence of HPτ, Aß and SVD on WMH severity. RESULTS: 36 human post-mortem right fixed cerebral hemispheres (mean age 84.4 ± 7.7 years; male: 16, female: 20) containing varying amounts of AD-pathology (AD: 23, controls: 13) underwent T2- weighted MRI with WMH assessed according to the age related white matter change scale (ARWMC). After dissection, using tissue samples from the frontal, temporal, parietal and occipital regions from the right hemisphere, we quantitatively assessed cortical HPτ and Aß pathology burden by measuring the percentage area covered by AT8 immunoreactivity (HPτ-IR) and 4G8 immunoreactivity (Aß-IR), and assessed the severity of WM SVD by calculating the sclerotic index (SI) of WM arteries/arterioles. HPτ-IR, Aß-IR, and SI were compared with ARWMC scores. HPτ-IR, Aß-IR and WM ARWMC scores were all significantly higher in AD cases compared to controls, while SI values were similar between groups. ARWMC scores correlated with HPτ-IR, Aß-IR and SI in various regions, however, linear regression revealed that only HPτ-IR was a significant independent predictor of ARWMC scores. CONCLUSIONS: Here we have shown that increasing cortical HPτ burden independently predicted the severity of WMH indicating its potentially important role in the pathogenesis of WM damage. Moreover, our findings suggest that in AD patients the presence of WMH may indicate cortical AD-associated pathology rather than SVD. Further studies are warranted to elucidate the pathological processes that lead to WM damage and to clarify if WMH may serve as a general biomarker for cortical AD-associated pathology.