Entries in alzheimer's (4)


Childhood epilepsy may be associated with increased β-amyloid accumulation in adulthood

Adults with childhood-onset epilepsy appear to have increased β-amyloid (Aβ) plaque accumulation compared to healthy controls, according to a recently published study conducted in Finland [1]. Brain Aβ plaque deposition was analyzed in 41 participants from a cohort of late middle- aged individuals with childhood-onset epilepsy and 46 matched controls using carbon 11-labeled Pittsburgh Compound B (PiB) positron emission tomography (PET) [1].  Aβ plaque accumulation, a well- known hallmark of Alzheimer’s disease (AD), occurs in the brain years before the appearance of the first cognitive symptoms [2]. The participants with childhood-onset epilepsy are involved in the Turku Adult Childhood Onset Epilepsy TACOE study [3], which has followed them for 5 decades.

Childhood epilepsy was associated with increased PiB uptake compared to controls [1]. In a semi-quantitative analysis, the AD risk gene, APO ε4, together with idiopathic epilepsy, was also found to be associated with increased PiB uptake [1]. The findings are noteworthy as the effects of childhood epilepsy on the brain and cognition later in life are not well understood. Future studies are needed to examine whether childhood epilepsy might be a risk factor for AD. Well known risk factors for AD include Down syndrome, genetic abnormalities, cardiovascular disease and traumatic brain injury [2, 4]. AD is the most common form of dementia and there is no treatment [2]. At present, an estimated 5.4 million Americans have Alzheimer's disease [2].



 [1] Joutsa J, Rinne JO, Hermann B, Karrasch M, Anttinen A, Shinnar S, Sillanpää M. Association Between Childhood-Onset Epilepsy and Amyloid Burden 5 Decades Later. JAMA Neurol. 2017;74(5):583-590.

[2] Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016;12(4):459-509.

[3] Sillanpää M, Jalava M, Kaleva O, Shinnar S. Long-term prognosis of seizures with onset in childhood. N Engl J Med. 1998;338(24):1715-22.

[4] Zigman WB, Lott IT. Alzheimer's disease in Down syndrome: neurobiology and risk. Ment Retard Dev Disabil Res Rev. 2007;13(3):237-46.


Non-invasive gamma oscillations show promise for reducing amyloid plaque

It is well established that Alzheimer’s disease (AD) is a fatal neurodegenerative disorder, which currently afflicts ~5.4 million Americans1. There are five FDA drugs approved to treat the debilitating symptoms of AD1, but no therapeutic to date can alleviate the underlying pathology. Recently, solanezumab, an experimental AD drug developed by Eli Lilly, failed to significantly slow the progression of cognitive decline in a phase 3 clinical trial2. Failure of this AD drug, and many others, is complicated by both the heterogeneity of AD and the extensive anatomical damage caused by the disease. A common hypothesis is that by the time AD symptoms emerge, neurological injury is beyond repair. To circumvent these issues, ideal AD treatments would be non-toxic, non-invasive, and prophylactic.
A recent report from Iaccarino and Singer et al. identified a non-invasive light-based intervention to reduce Aβ plaque formation (a hallmark of AD pathology) in AD mouse models3. This study established a link between gamma waves (a particular type of neural oscillation) and AD-related neurotoxicity. First, the authors determined that gamma waves were reduced in the hippocampus of pre-symptomatic AD mice (5XFAD model) as compared to wild-type controls, through electrophysiological recordings. To better understand the function of gamma waves, mice were engineered using optogenetics to produce 40 hertz (Hz) gamma oscillations upon pulses of light in a specific region of the brain (fast-spiking parvalbumin interneurons). One hour of gamma wave production was sufficient to reduce Aβ protein levels by ~40% as determined by enzyme-linked immunosorbent assays (ELISA) and immunohistochemistry (IHC). Next, authors investigated gene expression profiles altered by gamma wave production through RNA sequencing. Interestingly, genes associated with the engulfing state of microglia (immune cells of the brain) were enriched. As determined by IHC, microglia were enlarged and co-localized with Aβ plaques, suggesting that gamma waves stimulated microglial-mediated phagocytosis of Aβ.
To further the application of these findings, the authors engineered a 40 Hz light flickering paradigm to stimulate gamma waves in the mouse visual cortex non-invasively. Analogous to the optogenetic approach, one hour of light flicker intervention reduced Aβ protein levels in the visual cortex of AD and wild-type mice by 20-58%, as determined by ELISA. These effects were acute (lasting less than twenty-four hours) and constrained to the visual cortex (Aβ protein was not reduced in the hippocampus). In AD mice, the light flicker intervention also resulted in enlarged microglia that engulfed Aβ protein, as determined by IHC and fluorescence-activated cell sorting combined with ELISA. Finally, the authors investigated whether the light flicker intervention had utility in mice with advanced Aβ plaque formation. One hour of light flicker intervention for seven consecutive days resulted in reduction of Aβ plaque by ~67% and also reduced Tau phosphorylation (another hallmark of AD pathology).
Taken together this extensive mechanistic study provides a promising foundation for non-invasive AD treatment. Moving forward it will be important to explore the long-term effects of 40 Hz light flickering on plaque load, brain atrophy, cognition, and survival time. Future studies combining transcranial magnetic stimulation to produce 40 Hz gamma oscillations and amyloid positron emission tomography imaging in humans could further determine the in vivo relationship between gamma waves and Aβ plaque formation in AD patients.
1) Alzheimer’s Association, http://www.alz.org/research/overview.asp, 3 November 2016.
2) New York Times, “Eli Lilly’s Experimental Alzheimer’s Drug Fails in Large Trial”,  http://www.nytimes.com/2016/11/23/health/eli-lillys-experimental-alzheimers-drug-failed-in-large-trial.html?_r=0, 3 November 2016. 
3) Iaccarino and Singer et al. (2016) Gamma frequency entrainment attenuates amyloid load and modifies microglia Nature. 

Complement Proteins May Provide a Gateway to Early Alzheimer’s Disease Therapeutics

Complement Proteins May Provide a Gateway to Early Alzheimer’s Disease Therapeutics

The classical complement pathway recognizes pathogens and uses macrophage-mediated phagocytosis to fight infection (1). In the brain, the complement pathway prunes synapses through microglia-mediated phagocytosis to fine-tune neuronal development (1). However, this process can go awry if it is activated later in life. Recently, the complement pathway has garnered a lot of attention for its connection to schizophrenia.  Specifically, a landmark study by Sekar et al showed that the very highly associated schizophrenia risk allele, complement component 4A (C4A), resulted in more C4A protein production in schizophrenic brain tissue (2). Importantly, the authors found that C4 deficiency reduces synaptic pruning in mice (2). This result provided mechanistic rationale for the pronounced synaptic loss experienced by schizophrenic patients. Moving forward, it will be very interesting to determine whether overexpression of C4 increases synaptic pruning in rodent models, as too much pruning is the expected phenotype in schizophrenia.

Beyond schizophrenia, the complement pathway was further tied to synaptic pruning in early Alzheimer’s disease (AD) through elegant work by Hong et al (3). Using super-resolution structured illumination microscopy (SIM, ~150-300nm resolution) in a mouse model of AD, the authors showed that complement component 1q (C1q) expression was increased in the dentate gyrus and frontal cortex (3). Increased C1q expression was localized to synapses and dependent on Aβ expression (3). In wildtype mice, administration of soluble oligomeric Aβ reduced synapse number via the complement pathway, as Aβ had no effect in C1q knockout mice (3). This result indicated that the complement pathway may propagate early AD pathology, as the effects of C1q on synapse loss were mediated before Aβ plaque deposition (a hallmark of late-stage AD). Perhaps the most exciting result from this study was demonstrated by biologic and genetic targeting of complement proteins. In wild type mice, administration of a C1q antibody rescued synapse loss and neuronal function (as determined by LTP) in the presence of oligomeric Aβ (3) (Figure, taken from Hong et al). Further, in an AD mouse model, genetic knockout of downstream complement component 3 (C3) rescued synapse loss (3). These results highlight the therapeutic potential of complement inhibitors for early-stage AD treatment.

Together these studies illuminate an entry point to prevent aberrant synaptic pruning. I look forward to future studies investigating the effects of complement inhibition on memory and learning behaviors in schizophrenia and AD models.


1) Stephan AH, Barres BA, and Stevens B, Annu Rev Neurosci, 2012.

2) Sekar A et al., Nature, 2016.

3)Hong S et al., Science, 2016.


Nanoparticle antioxidants offer potential Alzheimer’s therapy

Mitochondria have been known as a cell’s power plants. The abnormal generation of reactive oxygen species (ROS) from dysfunctioning mitochondria can cause neuronal cell death. This pathologic process is a key factor to a number of neurodegenerative diseases, including Alzheimer’s disease (AD). Amyloid-β peptides, which are believed to cause AD, can interact with resident proteins inside mitochondria, inducing abnormal production of ROS. Thus, ROS scavengers, such as antioxidant molecules, targeting mitochondria would be useful for prevention and early state treatment of AD.

A research team lead by Taeghwan Hyeon designed and synthesized triphenylphosphonium-conjugated ceria (CeO2) nanoparticles (TPP-ceria NPs), which can selectively localize in mitochondria and behave as strong ROS scavengers. These nanoparticles function in a recyclable manner by shuttling between Ce(III) and Ce(IV) oxidation states. The study of an AD mouse model indicates that the nanoparticles effectively suppress neuronal cell death by protecting them from ROS. This research has paved the road for the development of novel strategy to prevent and treat AD and other neurodegenerative diseases. 



ACS Nano 2016, 10, 2860−2870.