Neuroscience Forefront ReviewSeizures in Alzheimer’s disease
Introduction
Seizures and neuronal network imbalances have recently been implicated in the development of cognitive deficits in a subset of Alzheimer’s disease (AD) patients (Rabinowicz et al., 2000, Palop and Mucke, 2009). Understanding the contribution of seizure-driven neuronal network dysfunction to AD may provide new insight for therapeutic strategies (Scharfman, 2012, Chin and Scharfman, 2013). Work linking amyloid precursor protein (APP), a protein important in the development of AD pathology, to epileptiform activity suggests these two diseases may be more tightly connected than previously assumed (Cabrejo et al., 2006, Born et al., 2014). This review focuses on findings from human patient and mouse model studies that examine the connection between seizures and AD and explores the possibility of treating AD patients with anti-epileptic drugs.
Section snippets
Co-morbidity of AD and seizures suggests common pathological mechanisms
AD affects an estimated 5.2 million Americans, is currently the sixth leading cause of death, and may contribute to almost as many deaths as caused by cancer (Thies and Bleiler, 2013, James et al., 2014). Age is the greatest risk factor for AD, with the majority of patients having a late-onset, sporadic form of the disease (Thies and Bleiler, 2013). AD is characterized by cognitive impairment and memory loss that typically begins with difficulty recalling recent events (Thies and Bleiler, 2013
Dominant familial AD often presents with seizure or myoclonus co-morbidity
A small percentage of patients (∼1%) inherit AD through autosomal dominant mutations in 3 genes (APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN2) that result in amyloid-β (Aβ) peptide overproduction and alter the ratio of Aβ42 to Aβ40 produced. Researchers have identified 185 mutations in PSEN1, and these mutations account for the majority of inherited early-onset familial AD (EOFAD) cases (Campion et al., 1999, Janssen et al., 2003). Conversely, only 33 mutations have been documented in APP
Abnormal network activity in mouse models of AD
To recreate AD pathology that develops over decades in human patients, researchers have made transgenic or knockin mice with one or more mutations found in EOFAD. Although mouse APP processing does not perfectly recapitulate human APP processing, the introduction of genetic mutations from the EOFAD pedigrees reproduces the cognitive decline and amyloid plaques within the animal’s short lifespan (Hsiao et al., 1996, Sanchez et al., 2012, Fowler et al., 2014). It should be noted that transgenic
APP and Aβ contribute to electrical imbalances
During normal development, processing of full-length APP results in multiple cleavage products. The non-amyloidogenic pathway begins with α-secretase cleavage, which cuts within the Aβ domain and produces extracellular soluble APPα (sAPPα) and a transmembrane α C-terminal fragment (CTFα). The CTFα is then sequentially processed by γ-secretase cleavage to release P3 and APP intracellular domain (AICD). Aβ peptide is produced through amyloidogenic processing, which requires β-secretase cleavage
Targeting cognitive dysfunction in AD with antiepileptic drugs
Preclinical studies of anti-epileptic drugs in mouse models and AD patients are another measure of support for a common mechanistic pathway between the two diseases. The anti-epileptic drug valproic acid (VPA) has been identified as a potential treatment for AD using APdE9 mice (Ziyatdinova et al., 2011). In pre-clinical studies VPA treatment reduced Aβ production both in vitro in APPSwe transfected HEK293 cells and in vivo in PDAPP tg mice (Su et al., 2004). VPA treatment also reduced amyloid
Conclusions
The link between seizures and AD has been established in studies examining EOFAD patients, sporadic AD patients, and AD mouse models. Work focused on the relationship between AD and epilepsy has identified APP/Aβ as a possible mechanistic link between the two disorders. There are a variety of other neurodegenerative and neurodevelopmental disorders that are linked to APP/Aβ dysregulation and often involve seizures including traumatic brain injury, Fragile X syndrome, DS, autism, and Parkinson’s
Acknowledgements
HAB was supported by funds from the Federal Work Study Program, seed funds from the Baylor College of Medicine to Joanna L. Jankowsky, and by BrightFocus Foundation Alzheimer’s Disease research grant A2010097 to Joanna L. Jankowsky. The author thanks Dr. Stacy Grunke for her critical reading of the manuscript and Dr. Joanna Jankowsky and other members of the Jankowsky lab for their helpful comments. The author declares no financial conflicts of interest with the contents of this review.
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2021, Ageing Research ReviewsCitation Excerpt :In vivo cellular-level imaging and electrophysiology of neurons in the direct vicinity of amyloid plaques showed a significant proportion of neurons with abnormally increased activity (Busche et al., 2015, 2012a; Grienberger et al., 2012; Keskin et al., 2017; Liebscher et al., 2016; Maier et al., 2014; Rudinskiy et al., 2012; Scala et al., 2015; Šišková et al., 2014; Xu et al., 2015). Additional support for a role of amyloid-related neuronal hyperexcitability was also provided from long-term video-EEG recordings demonstrating that many Aβ-bearing mouse models exhibit epileptiform discharges as well as spontaneous recurrent seizures (Born, 2015; Palop et al., 2007). Importantly, it is increasingly recognized that many patients with AD exhibit epileptiform and seizure activity (Vossel et al., 2017).
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