Cerebral hypoperfusion reduces tau accumulation

Abstract

Objective: Alzheimer's disease (AD) often coexists with cerebrovascular diseases. However, the impact of cerebrovascular diseases such as stroke on AD pathology remains poorly understood.

Methods: This study examines the correlation between cerebrovascular diseases and AD pathology. The research was carried out using clinical and neuropathological data collected from the National Alzheimer's Coordinating Center (NACC) database and an animal model in which bilateral common carotid artery stenosis surgery was performed, following the injection of tau seeds into the brains of wild-type mice.

Results: Analysis of the NACC database suggests that clinical stroke history and lacunar infarcts are associated with lower neurofibrillary tangle pathology. An animal model demonstrates that chronic cerebral hypoperfusion reduces tau pathology, which was observed in not only neurons but also astrocytes, microglia, and oligodendrocytes. Furthermore, we found that astrocytes and microglia were activated in response to tau pathology and chronic cerebral hypoperfusion. Additionally, cerebral hypoperfusion increased a lysosomal enzyme, cathepsin D.

Interpretation: These data together indicate that cerebral hypoperfusion reduces tau accumulation likely through an increase in microglial phagocytic activity towards tau and an elevation in degradation through cathepsin D. This study contributes to understanding the relationship between tau pathology and cerebrovascular diseases in older people with multimorbidity.

Figure 1

Clinical stroke and lacune pathology are associated with fewer tau pathologies. (A) Effects of remote stroke history on Braak NFT stage in whole neuropathologically‐examined subjects (n = 4512), adjusted for age at death, sex, race, APOE4, and cognitive/dementia status. Effects of vascular pathologies, “infarcts and lacunes” (B) or “One or more lacunes” (C), on Braak NFT stage in subjects with AD‐type dementia (n = 2630), adjusted for age at death, sex, race, and APOE4. Data are presented as the adjusted mean ± standard error of the mean. **P < 0.01, and ***P < 0.001; by Student's t‐test.

Figure 2

Chronic cerebral hypoperfusion reduced tau accumulation and increased white matter lesions in the Tau/BCAS mice. (A) Experimental schedule. (B) Representative pictures of AT8 staining and (C) percentages of the AT8‐positive area were compared among groups. *P < 0.05 and **P < 0.01, as determined by one‐way ANOVA followed by the Tukey Kramer HSD test (n = 15–19 in each group). (D) Klüver‐Barrera staining and (E) grade of white matter lesions were compared among groups. Data are shown as a box‐and‐whisker plot (boxplot) with individual data points. *P < 0.05 and **P < 0.01, as determined by Steel‐Dwass test (n = 17–19 in each group). Scale bar = 50 μm.

Figure 3

Behavioral characteristics of the Tau/BCAS mice. (A) Total distance traveled and (B) mobile time in the open‐field test. *P < 0.05, by Steel‐Dwass test. (C) Average escape latency during the training period of the Morris water maze test. *P < 0.05 compared with the scores on day 2, as determined by repeated‐measures one‐way ANOVA followed by Tukey HSD test. (D) Time spent in the target quadrant during the probe test. Data are shown as boxplots with individual data points (A, B, D), or as means ± standard error of the mean (C) (n = 17–19 in each group). ns, not significant.

Figure 4

Co‐localization of phospho‐tau and glial markers in the hippocampus and quantification of glial cell marker positive areas in the Tau/BCAS mice. (A) Double staining for GFAP (red) and phospho‐tau (Thr212, green) and (B) phospho‐tau (AT8, red) and Iba1 (green). Scale bar = 20 μm. (C–F) Immunoreactive areas of GFAP (C, D) and Iba1 (E, F) were compared among groups. Data are shown as boxplots with individual data points. *P < 0.05 and **P < 0.01, as determined by Steel‐Dwass test (n = 10 in each group). Scale bar = 50 μm.

Figure 5

Chronic cerebral hypoperfusion increased immunoreactivities of cathepsin D in the Tau/BCAS mice. (A) Double staining for AT8 (red) and CTSD (green). Scale bar = 20 μm. (B) CTSD immunoreactivities are shown with green fluorescence. Scale bar = 10 μm. (C) Quantified data of CTSD‐positive areas in the hippocampus were compared among groups. (D) Co‐localization of CTSD (cyan), AT8 (green), and Iba1 (red), in the hippocampus. Data are shown as boxplots with individual data points. *P < 0.05, as determined by Steel‐Dwass test (n = 10 in each group). Scale bar = 10 μm.