Abstract
The aging brain is often characterized by the presence of multiple comorbidities resulting in synergistic damaging effects in the brain as demonstrated through the interaction of Alzheimer’s disease (AD) and stroke. Gangliosides, a family of membrane lipids enriched in the central nervous system, may have a mechanistic role in mediating the brain’s response to injury as their expression is altered in a number of disease and injury states. Matrix-Assisted Laser Desorption Ionization (MALDI) Imaging Mass Spectrometry (IMS) was used to study the expression of A-series ganglioside species GD1a, GM1, GM2, and GM3 to determine alteration of their expression profiles in the presence of beta-amyloid (Aβ) toxicity in addition to ischemic injury. To model a stroke, rats received a unilateral striatal injection of endothelin-1 (ET-1) (stroke alone group). To model Aβ toxicity, rats received intracerebralventricular (icv) injections of the toxic 25-35 fragment of the Aβ peptide (Aβ alone group). To model the combination of Aβ toxicity with stroke, rats received both the unilateral ET-1 injection and the bilateral icv injections of Aβ₂₅₋₃₅ (combined Aβ/ET-1 group). By 3 d, a significant increase in the simple ganglioside species GM2 was observed in the ischemic brain region of rats who received a stroke (ET-1), with or without Aβ. By 21 d, GM2 levels only remained elevated in the combined Aβ/ET-1 group. GM3 levels however demonstrated a different pattern of expression. By 3 d GM3 was elevated in the ischemic brain region only in the combined Aβ/ET-1 group. By 21 d, GM3 was elevated in the ischemic brain region in both stroke alone and Aβ/ET-1 groups. Overall, results indicate that the accumulation of simple ganglioside species GM2 and GM3 may be indicative of a mechanism of interaction between AD and stroke.
Highlights
IntroductionPatients often simultaneously experience two or more medical conditions which complicates the study of age-related neurodegenerative diseases such as Alzheimer’s disease (AD)
As we age, our brains become more vulnerable to diseases and injuries
Based on evidence from the literature [4,5,7,9,14,15,16,18,19], the observed increase in simple gangliosides GM2 and GM3 in the stroke region of the Aβ/ET-1 combined group at both 3 and 21 d after surgery is indicative of a more severe pathological response compared to ET-1 alone and Aβ alone as GM2 has been shown to be elevated immediately after TBI [14] and accumulations of GM3 has been shown to increase toxicity and induce apoptosis in cells [15,16,17,18,19]
Summary
Patients often simultaneously experience two or more medical conditions which complicates the study of age-related neurodegenerative diseases such as Alzheimer’s disease (AD). When multiple conditions are present simultaneously (comorbidity), synergistic effects on pathology and cognitive outcomes can be observed as demonstrated in the case of AD and stroke. AD and stroke comorbidity has been observed in carriers of the APOE4 gene. Data from the Canadian Study of Health and Aging (CSHA) showed that prevalence of dementia was increased among those who had a history of stroke and were APOE4 carriers [2]. Another study demonstrated that APOE4 carriers with a history of stroke were five times more likely to develop dementia than APOE4 carriers without such a history [3]. A potential mediator for this interaction may lie within a family of cellular membrane lipids known as gangliosides
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