Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events

Abstract

BackgroundVascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind only Alzheimer’s disease (AD); however, VCID is commonly found as a co-morbidity with sporadic AD. We have previously established a mouse model of VCID by inducing hyperhomocysteinemia in both wild-type and amyloid depositing mice. While we have shown the time course of neuropathological events in the wild-type mice with hyperhomocysteinemia, the effect of amyloid deposition on this time course remains unknown; therefore, in this study, we determined the time course of neuropathological changes in our mouse model of hyperhomocysteinemia-induced VCID in amyloid depositing mice.MethodsAPP/PS1 mice were placed on either a diet deficient in folate and vitamins B6 and B12 and enriched in methionine to induce hyperhomocysteinemia or a control diet for 2, 6, 10, 14, or 18 weeks. Immunohistochemistry and gene expression analysis were used to determine neuroinflammatory changes. Microhemorrhages and amyloid deposition were analyzed using histology and, finally, behavior was assessed using the 2-day radial arm water maze.ResultsNeuroinflammation, specifically a pro-inflammatory phenotype, was the first pathological change to occur. Specifically, we see a significant increase in gene expression of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 12a by 6 weeks. This was followed by cognitive deficits starting at 10 weeks. Finally, there is a significant increase in the number of microhemorrhages at 14 weeks on diet as well as redistribution of amyloid from the parenchyma to the vasculature.ConclusionsThe time course of these pathologies points to neuroinflammation as the initial, key player in homocysteine-induced VCID co-morbid with amyloid deposition and provides a possible therapeutic target and time points.

Microglial-associated responses to comorbid amyloid pathology and hyperhomocysteinemia in an aged knock-in mouse model of Alzheimer’s disease

“…Overall, the cytokine data are consistent with previous studies that indicate an enhancement of proinflammatory responses in either WT or AD model mice in response to HHcy [20][21][22]32]. Despite this, the magnitude of the effect appears to be much smaller in the present case, and there are several possibilities for this apparent discrepancy.…”

“…This implies that interstitial levels of soluble Aβ are being kept in equilibrium via increased plaque formation, consistent with the notion that sequestration into plaques can be a protective response against the more toxic soluble Aβ species [ 31 ]. Our data align with the hypothesis that HHcy can enhance AD risk by increasing overall amyloid burden, a finding that has been replicated across models of AD and under different methods of HHcy-induction [ 21 , 32 – 34 ]. Importantly, this appears reflective of what occurs in patient populations, where plasma Aβ positively correlates with homocysteine levels and elevated Hcy is also associated with higher brain Aβ accumulation and CAA pathology [ 35 – 38 ].…”

Microglial-associated responses to comorbid amyloid pathology and hyperhomocysteinemia in an aged knock-in mouse model of Alzheimer’s disease

“…It is worth noting, however, that at least one study has observed an increase in plaque-associated dystrophic neurites in association with reduced CCL3 [33] which suggests that its upregulation can in some cases be protective, although this may be a correlative rather than causative effect. In any event, the cytokine data herein are in contrast to previous studies that have reported a robust pro-inflammatory response to this diet in either WT or AD model mice [12][13][14]22].…”

“…amyloid burden in parenchyma and vasculature [13,[22][23][24]. This is reflective of what occurs in patient populations, where plasma Aβ positively correlates with homocysteine levels and elevated Hcy is also associated with higher brain Aβ accumulation and CAA pathology [25][26][27][28].…”

“…Further, recent research indicates that the P2ry12 receptor is crucial for microglial monitoring of neuronal functioning and the induction of neuroprotective responses [34]. enhance neuronal dysfunction is currently unknown; however, given reported additive effects on cognitive impairment caused by the presence of amyloid and HHcy pathologies [13,22], this seems likely.…”