Epigenetic conditioning induces intergenerational resilience to dementia in a mouse model of vascular cognitive impairment.

INTRODUCTION: Epigenetic stimuli induce beneficial or detrimental changes in gene expression, and consequently, phenotype. Some of these phenotypes can manifest across the lifespan-and even in subsequent generations. Here, we used a mouse model of vascular cognitive impairment and dementia (VCID) to determine whether epigenetically induced resilience to specific dementia-related phenotypes is heritable by first-generation progeny. METHODS: Our systemic epigenetic therapy consisted of 2 months of repetitive hypoxic "conditioning" (RHC) prior to chronic cerebral hypoperfusion in adult C57BL/6J mice. Resultant changes in object recognition memory and hippocampal long-term potentiation (LTP) were assessed 3 and 4 months later, respectively. RESULTS: Hypoperfusion-induced memory/plasticity deficits were abrogated by RHC. Moreover, similarly robust dementia resilience was documented in untreated cerebral hypoperfused animals derived from RHC-treated parents. CONCLUSIONS: Our results in experimental VCID underscore the efficacy of epigenetics-based treatments to prevent memory loss, and demonstrate for the first time the heritability of an induced resilience to dementia.

Intra- and intergenerational changes in the cortical DNA methylome in response to therapeutic intermittent hypoxia in mice.

Recent evidence from our laboratory documents functional resilience to retinal ischemic injury in untreated mice derived from parents exposed to repetitive hypoxic conditioning (RHC) before breeding. To begin to understand the epigenetic basis of this intergenerational protection, we used methylated DNA immunoprecipitation and sequencing to identify genes with differentially methylated promoters (DMGPs) in the prefrontal cortex of mice treated directly with the same RHC stimulus (F0-RHC) and in the prefrontal cortex of their untreated F1-generation offspring (F1-*RHC). Subsequent bioinformatic analyses provided key mechanistic insights into how changes in gene expression secondary to promoter hypo- and hypermethylation might afford such protection within and across generations. We found extensive changes in DNA methylation in both generations consistent with the expression of many survival-promoting genes, with twice the number of DMGPs in the cortex of F1*RHC mice relative to their F0 parents that were directly exposed to RHC. In contrast to our hypothesis that similar epigenetic modifications would be realized in the cortices of both F0-RHC and F1-*RHC mice, we instead found relatively few DMGPs common to both generations; in fact, each generation manifested expected injury resilience via distinctly unique gene expression profiles. Whereas in the cortex of F0-RHC mice, predicted protein-protein interactions reflected activation of an anti-ischemic phenotype, networks activated in F1-*RHC cortex comprised networks indicative of a much broader cytoprotective phenotype. Altogether, our results suggest that the intergenerational transfer of an acquired phenotype to offspring does not necessarily require the faithful recapitulation of the conditioning-modified DNA methylome of the parent.

Intermittent streptozotocin administration induces behavioral and pathological features relevant to Alzheimer's disease and vascular dementia.

RATIONALE: Diabetes mellitus (DM) is a major risk factor for Alzheimer's disease and vascular dementia. Few animal models exist that focus on the metabolic contributions to dementia onset and progression. Thus, there is strong scientific rationale to explore the effects of streptozotocin (STZ), a diabetogenic compound, on vascular and inflammatory changes within the brain. OBJECTIVE AND METHODS: The present study was designed to evaluate the effect of staggered, low-dose administration of STZ on behavioral and cognitive deficits, neuroinflammation, tau pathology, and histopathological alterations related to dementia. RESULTS: Staggered administration (Days 1, 2, 3, 14, 15) of streptozotocin (40 mg/kg/mL) induced a diabetic-like state in mice, resulting in sustained hyperglycemia. STZ-treated animals displayed memory deficits in the novel object recognition task as well as increased tau phosphorylation and increased neuroinflammation. Additionally, STZ led to altered insulin signaling, exhibited by decreased plasma insulin and decreased levels of insulin degrading enzyme and pAKT within the hippocampus. CONCLUSIONS: STZ-treated animals exhibit cognitive deficits and histopathological changes seen in dementia. This model of dementia warrants continued investigation to better understand the role that DM plays in dementia-related alterations.