Role of age and neuroinflammation in the mechanism of cognitive deficits in sickle cell disease

Abstract

This study aims to determine whether sickle cell mice could recapitulate features of cognitive and neurobehavioral impairment observed in sickle cell patients and whether neuroinflammation could be a potential therapeutic target as in other non-sickle cell disease-related cognitive dysfunction. Cognitive (learning and memory) and behavioral (anxiety) deficits in 13- and later 6-month-old male Townes humanized sickle cell (SS) and matched control (AA) mice were evaluated using novel object recognition (NOR) and fear conditioning tests. Immunohistochemistry was performed to quantify peripheral immune cell (CD45+) and activated microglia (Iba1+) as markers of neuroinflammation in the dentate and peri-dentate gyrus areas. We evaluated cell fate by measuring 5'-bromodeoxyuridine and doublecortin fluorescence and phenotyped proliferating cells using either glial fibrillary acid protein (GFAP+), neuronal nuclei (NeuN+), CD45+, and Iba1+. In addition, Golgi-Cox staining was used to assess markers of neuroplasticity (dendritic spine density and morphology and density of dendrite arbors) on cortical and hippocampal pyramidal neurons. Compared to matched AA controls, 13-month-old SS mice showed significant evidence of cognitive and behavioral deficit on NOR and fear conditioning tests. Also, SS mice had significantly higher density of CD45+ and activated microglia cells (i.e. more evidence of neuroinflammation) in the dentate and peri-dentate gyrus area. Additionally, SS mice had significantly lower dendritic spine density, but a higher proportion of immature dendritic spines. Treatment of 13-month-old SS mice with minocycline resulted in improvement of cognitive and behavioral deficit compared to matched vehicle-treated SS mice. Also, treated SS mice had significantly fewer CD45+ and activated microglia cells (i.e. less evidence of neuroinflammation) in the dentate and peri-dentate gyrus, as well as a significant improvement in markers of neuroplasticity. Impact statement This study provides crucial information that could be helpful in the development of new or repurposing of existing therapies for the treatment of cognitive deficit in individuals with sickle cell disease (SCD). Its impact is in demonstrating for the first time that neuroinflammation and along with abnormal neuroplasticity are among the underlying mechanism of cognitive and behavioral deficits in SCD and that drugs such as minocycline which targets these pathophysiological mechanisms could be repurposed for the treatment of this life altering complication of SCD.

Sickle cell disease as an accelerated aging syndrome

“…[47][48][49] Abnormalities of sphingolipids metabolism, especially increased acid sphingomyelinase, have been shown to play a role in age-related neuroinflammation and neurodegenerative changes. 50,51 Recent studies in animal models of SCD have also shown that presence of cognitive impairment in 6 months 52 and in 13 months 53 old mice have cellular evidence of neuroinflammation and neurodegeneration as observed in aged non-sickle cell mice (described earlier). Taken together, neurological injuries associated with SCD at a relatively young age suggest accelerated cerebrovascular aging.…”

Molecular and environmental contributors to neurological complications in sickle cell disease

“…107 In addition, Hardy et al . 15 observed increased microglial activation, decreased dendrite arbors and dendritic spine density (markers of structural neuroplasticity), increased proportion of immature dendritic spines (a marker of functional neuroplasticity), and increased density of peripherally derived CD45 + mononuclear cells in the hippocampus of aged Townes humanized SCA mice; all of these pathological changes correlated with poor cognitive function compared to younger SCA and healthy control mice. Both the behavioral changes and histological changes were abrogated by treatment with minocycline, a tetracycline antibiotic with antineuroinflammatory activities that effectively crosses the blood–brain barrier.…”

“…In addition, treated SCD mice had significant improvements on learning and memory tasks compared to untreated mice; the treated mice scored no differently than age and sex-matched controls. 15 The largest human trial to date, the Minocycline in Alzheimer Disease Efficacy (MADE) Trial, evaluated the role of minocycline at two dosing strategies to slow the rate of cognitive decline in individuals with mild Alzheimer’s disease over 24 months of follow-up; although no statistically significant difference was observed when comparing the patients treated at either minocycline dose versus placebo, a trend toward a significantly lower rate of decline was seen when comparing the higher-dose versus low-dose minocycline therapy. 142 In addition, the study used the standardized Mini-Mental State Examination (MMSE) as their cognitive outcome measure; however, the MMSE has very limited ability to diagnose mild cognitive impairment and does not actually examine executive function.…”

Perspectives on Cognitive Phenotypes and Models of Vascular Disease

“…A recent report demonstrated cognitive deficit in a sickle cell disease mouse model. 19 Patients with chronic pulmonary disease are at higher risk of developing dementia including patients with chronic obstructive pulmonary disease. 20,21 Additionally, vascular abnormalities in this group of patients are not limited to the lung and include multi-system vascular deficiencies in other organs including brain, kidney, and heart which complicate the course and outcomes of the disease in these patients.…”