Abstract TP276: Mild Short-term Hypertension Exacerbates Amyloid Pathology and Microhemorrhages in Mouse Model of Amyloidosis

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Introduction: Multiple epidemiological studies link vasculature-affecting disorders, such as hypertension, diabetes mellitus, kidney failure and stroke, with dementia and Alzheimer’s disease (AD). Hypertension is an important modifiable risk factor for late-onset sporadic AD, and often associated with increased incidents of intracerebral hemorrhages (ICH) and cerebral amyloid angiopathy (CAA).

Hypothesis: To examine the association between short-term mild experimental hypertension and the progression of AD pathology later in life, we pharmacologically induced mild chronic hypertension in the APP/Tg2576 mouse model of AD.

Methods: Twenty-month old APP/Tg2576 mice (n=6) received N-Nitro-l-arginine methyl ester hydrochloride (L-NAME) in drinking water, for the daily doses of 100 mg/kg body weight for each mouse. Control mice (n=4) had regular drinking water. Treatment continued for 4 weeks. Blood pressure was measured 4 days before termination of the experiment with tail-cuff system (CODA). At the end of experiment mouse brains were collected and analyzed for amyloid-related AD pathology, inflammatory markers of glial activation and cerebrovascular pathology. Differences between groups were tested by t-test.

Results: There was a significant mild increase in diastolic (109±5.1 vs 123±2.4 mmHg, p<0.05) and mean blood pressure (118±5.9 vs 135±2.8 mmHg, p<0.05) after 3 1/2 weeks of L-NAME treatment. Increased blood pressure had not induced stroke symptoms in treated mice. After 4 weeks of L-NAME treatment mice showed significant increase in amyloid-beta load, revealed by 20.1 antibody staining (6.09±1.12 vs 9.35±0.63 %, p<0.05). Short-term mild hypertension had not affected microglia (Iba1) and astrocytes (GFAP) activation. Short-term mild hypertension did not induced new microbleeds in Tg2576 mice, however, there was a strong trend (p=0.123) towards the increased size of pre-existing microbleeds.

Conclusions: Our results suggest that short-term mild experimental hypertension late in life in APP/Tg mouse model of amyloidosis exacerbated amyloid pathology and cerebral microhemorrhages. Managing the blood pressure in the population at risk of AD should be considered as a potential preventive therapy for this neurological disorder.

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