Chronic evoked seizures in young pre-symptomatic APP/PS1 mice induce serotonin changes and accelerate onset of Alzheimer's disease-related neuropathology.

OBJECTIVE: Hyperexcitability is intimately linked to Alzheimer's disease (AD) pathology, but the precise timing and contributions of neuronal hyperexcitability to disease progression is unclear. Seizure induction in rodent AD models can uncover new therapeutic targets. Further, investigator-evoked seizures can directly establish how hyperexcitability and AD-associated risk factors influence neuropathological hallmarks and disease course at presymptomatic stages. METHODS: Corneal kindling is a well-characterized preclinical epilepsy model that allows for precise control of seizure history to pair to subsequent behavioral assessments. 2-3-month-old APP/PS1, PSEN2-N141I, and transgenic control male and female mice were thus sham or corneal kindled for 2 weeks. Seizure-induced changes in glia, serotonin pathway proteins, and amyloid ß levels in hippocampus and prefrontal cortex were quantified. RESULTS: APP/PS1 females were more susceptible to corneal kindling. However, regardless of sex, APP/PS1 mice experienced extensive seizure-induced mortality versus kindled Tg- controls. PSEN2-N141I mice were not negatively affected by corneal kindling. Mortality correlated with a marked downregulation of hippocampal tryptophan hydroxylase 2 and monoamine oxidase A protein expression versus controls; these changes were not detected in PSEN2-N141I mice. Kindled APP/PS1 mice also exhibited soluble amyloid ß upregulation and glial reactivity without plaque deposition. SIGNIFICANCE: Evoked convulsive seizures and neuronal hyperexcitability in pre-symptomatic APP/PS1 mice promoted premature mortality without pathological Aß plaque deposition, whereas PSEN2-N141I mice were unaffected. Disruptions in serotonin pathway metabolism in APP/PS1 mice was associated with increased glial reactivity without Aß plaque deposition, demonstrating that neuronal hyperexcitability in early AD causes pathological Aß overexpression and worsens long-term outcomes through a serotonin-related mechanism.

Loss of normal Alzheimer's disease-associated Presenilin 2 function alters antiseizure medicine potency and tolerability in the 6-Hz focal seizure model.

Introduction: Patients with early-onset Alzheimer's disease (EOAD) experience seizures and subclinical epileptiform activity, which may accelerate cognitive and functional decline. Antiseizure medicines (ASMs) may be a tractable disease-modifying strategy; numerous ASMs are marketed with well-established safety. However, little information is available to guide ASM selection as few studies have rigorously quantified ASM potency and tolerability in traditional seizure models in rodents with EOAD-associated risk factors. Presenilin 2 (PSEN2) variants evoke EOAD, and these patients experience seizures. This study thus established the anticonvulsant profile of mechanistically distinct ASMs in the frontline 6-Hz limbic seizure test evoked in PSEN2-knockout (KO) mice to better inform seizure management in EOAD. Methods: The median effective dose (ED50) of prototype ASMs was quantified in the 6-Hz test in male and female PSEN2-KO and wild-type (WT) C57BL/6J mice (3-4 months old). Minimal motor impairment (MMI) was assessed to estimate a protective index (PI). Immunohistological detection of cFos established the extent to which 6-Hz stimulation activates discrete brain regions in KO vs. WT mice. Results: There were significant genotype-related differences in the potency and tolerability of several ASMs. Valproic acid and levetiracetam were significantly more potent in male KO than in WT mice. Additionally, high doses of valproic acid significantly worsened MMI in KO mice. Conversely, carbamazepine was significantly less potent in female KO vs. WT mice. In both male and female KO mice vs. WTs, perampanel and lamotrigine were equally potent. However, there were marked genotype-related shifts in PI of both carbamazepine and perampanel, with KO mice exhibiting less MMI at the highest doses tested. Gabapentin was ineffective against 6-Hz seizures in KO mice vs. WTs without MMI changes. Neuronal activation 90 min following 6-Hz stimulation was significantly increased in the posterior parietal association cortex overlying CA1 and in the piriform cortex of WT mice, while stimulation-induced increases in cFos immunoreactivity were absent in KO mice. Discussion: Acute ASM potency and tolerability in the high-throughput 6-Hz test may be significantly altered with loss of normal PSEN2 function. Seizures in discrete EOAD populations may benefit from precisely selected medicines optimized for primary ASM pharmacological mechanisms.

Chronic evoked seizures in young pre-symptomatic APP/PS1 mice induce serotonin changes and accelerate onset on Alzheimer's disease-related neurpathology.

OBJECTIVE: People with early-onset Alzheimer's disease (AD) are at elevated seizure risk. Further, chronic seizures in pre-symptomatic stages may disrupt serotonin pathway-related protein expression, precipitating the onset of AD-related pathology and burden of neuropsychiatric comorbidities. METHODS: 2-3-month-old APP/PS1, PSEN2-N141I, and transgenic control mice were sham or corneal kindled for 2 weeks to model chronic seizures. Seizure-induced changes in glia, serotonin pathway proteins, and amyloid beta; levels in hippocampus and prefrontal cortex were quantified. RESULTS: APP/PS1 mice experienced worsened mortality versus kindled Tg- controls. APP/PS1 females were also more susceptible to chronic kindled seizures. These changes correlated with a marked downregulation of hippocampal tryptophan hydroxylase 2 and monoamine oxidase A protein expression compared to controls; these changes were not detected in PSEN2-N141I mice. Kindled APP/PS1 mice exhibited amyloid beta; overexpression and glial overactivity without plaque deposition. PSEN2 protein expression was AD model-dependent. SIGNIFICANCE: Seizures evoked in pre-symptomatic APP/PS1 mice promotes premature mortality in the absence of pathological amyloid deposition. Disruptions in serotonin pathway metabolism are associated with increased glial reactivity and PSEN2 downregulation without amyloid beta; deposition. This study provides the first direct evidence that seizures occurring prior to amyloid beta, plaque accumulation worsen disease burden in an AD genotype-specific manner.

Can Old Animals Reveal New Targets? The Aging and Degenerating Brain as a New Precision Medicine Opportunity for Epilepsy.

Older people represent the fastest growing group with epilepsy diagnosis. For example, cerebrovascular disease may underlie roughly 30-50% of epilepsy in older adults and seizures are also an underrecognized comorbidity of Alzheimer's disease (AD). As a result, up to 10% of nursing home residents may take antiseizure medicines (ASMs). Despite the greater incidence of epilepsy in older individuals and increased risk of comorbid seizures in people with AD, aged animals with seizures are strikingly underrepresented in epilepsy drug discovery practice. Increased integration of aged animals into preclinical epilepsy drug discovery could better inform the potential tolerability and pharmacokinetic interactions in aged individuals as the global population becomes increasingly older. Quite simply, the ASMs on the market today were brought forth based on efficacy in young adult, neurologically intact rodents; preclinical information concerning the efficacy and safety of promising ASMs is not routinely evaluated in aged animals. Integrating aged animals more often into basic epilepsy research may also uncover novel treatments for hyperexcitability. For example, cannabidiol and fenfluramine demonstrated clear efficacy in syndrome-specific pediatric models that led to a paradigm shift in the perceived value of pediatric models for ASM discovery practice; aged rodents with seizures or rodents with aging-related neuropathology represent an untapped resource that could similarly change epilepsy drug discovery. This review, therefore, summarizes how aged rodent models have thus far been used for epilepsy research, what studies have been conducted to assess ASM efficacy in aged rodent seizure and epilepsy models, and lastly to identify remaining gaps to engage aging-related neurological disease models for ASM discovery, which may simultaneously reveal novel mechanisms associated with epilepsy.

Alzheimer's Disease and Epilepsy: A Perspective on the Opportunities for Overlapping Therapeutic Innovation.

Early-onset Alzheimer's disease (AD) is associated with variants in amyloid precursor protein (APP) and presenilin (PSEN) 1 and 2. It is increasingly recognized that patients with AD experience undiagnosed focal seizures. These AD patients with reported seizures may have worsened disease trajectory. Seizures in epilepsy can also lead to cognitive deficits, neuroinflammation, and neurodegeneration. Epilepsy is roughly three times more common in individuals aged 65 and older. Due to the numerous available antiseizure drugs (ASDs), treatment of seizures has been proposed to reduce the burden of AD. More work is needed to establish the functional impact of seizures in AD to determine whether ASDs could be a rational therapeutic strategy. The efficacy of ASDs in aged animals is not routinely studied, despite the fact that the elderly represents the fastest growing demographic with epilepsy. This leaves a particular gap in understanding the discrete pathophysiological overlap between hyperexcitability and aging, and AD more specifically. Most of our preclinical knowledge of hyperexcitability in AD has come from mouse models that overexpress APP. While these studies have been invaluable, other drivers underlie AD, e.g. PSEN2. A diversity of animal models should be more frequently integrated into the study of hyperexcitability in AD, which could be particularly beneficial to identify novel therapies. Specifically, AD-associated risk genes, in particular PSENs, altogether represent underexplored contributors to hyperexcitability. This review assesses the available studies of ASDs administration in clinical AD populations and preclinical studies with AD-associated models and offers a perspective on the opportunities for further therapeutic innovation.