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Links in the Pathogenesis of Down Syndrome and Alzheimer’s Disease
By Jorge Busciglio, Ph.D., and Maria Torres
Nearly 75% of middle-aged individuals with Down syndrome develop Alzheimer’s disease neuropathology, including amyloid beta (Aβ) plaques and neurofibrillary tangles. The high incidence of Alzheimer’s disease in Down syndrome offers a unique opportunity to further understand Alzheimer’s disease pathogenesis, identify biomarkers of cognitive decline and develop early treatments.
As noted by Dr. Ira Lott in a related article, development of Alzheimer’s disease in Down syndrome is related to the increased expression of the amyloid precursor protein (APP) gene, which is located on chromosome 21. APP is the precursor of Aβ, the main component of senile plaques and one of the hallmarks of Alzheimer’s disease pathology. Postmortem studies have shown that plaques and tangles develop as early as 30 years of age in persons with Down syndrome, but interestingly not all Down syndrome individuals with Alzheimer’s disease neuropathology develop symptoms of dementia. The early emergence of Alzheimer’s disease pathology in people with Down syndrome not only highlights the growing need for early treatments to halt the disease progression, but may also provide insights to prevent the development of Alzheimer’s disease.
In addition to the multiple medical and physical manifestations of Down syndrome (e.g., skeletal anomalies, craniofacial alterations, low muscle tone, increased incidence of congenital heart disease and seizures, abnormalities of the gastrointestinal track, and premature aging), the disorder is characterized by the presence of mild-to-moderate intellectual disability. Down syndrome individuals exhibit deficits in motor skills, language, learning and memory. Cognitive deficits are associated with morphological anomalies in the brain. Some of these abnormalities are observed in the structure of neuronal cells, and include decreased number and aberrant architecture of dendritic spines. Dendritic spines are small protrusions found in neuronal extensions called dendrites. Dendrites are the information input region of neurons, and dendritic spines constitute principal sites of connections between neurons called synapses. Defects in the shape of spines usually reflect structural alterations in synapses, which are believed to contribute to the malfunction of neuronal circuits in the brain and to intellectual disability in Down syndrome. The mechanisms involved in the structural alterations of dendritic spines in Down syndrome are not known.
Research in our laboratory is aimed at understanding the molecular mechanisms underlying dendritic spine pathology in Down syndrome. We are investigating the role of astrocytes, a type of glial cell in the brain, in spine defects. Astrocytes provide support for and modulate the function of neurons. We identified thrombospondin-1 (TSP-1), an astrocyte-secreted protein, as a critical factor that modulates dendritic spine development. Additional experiments showed that TSP-1 production is reduced in Down syndrome astrocytes. Reduced TSP-1 levels produce pathological changes in dendritic spine structure. These alterations can be prevented by addition of recombinant TSP-1, suggesting an important role for TSP-1 in the formation and modulation of dendritic spines. TSP-1 deficiency may be associated with defects in the number and morphology of spines seen in Down syndrome and other neurological disorders. In fact, defects in dendritic spine structure and function have been widely reported in Alzheimer’s disease patients and linked to neuronal dysfunction and cognitive impairment. These novel findings provide a mechanistic rationale for the exploration of TSP-1-based therapies to treat spine and synaptic pathology in Down syndrome and other neurological disorders.
We are also actively researching the mechanisms of mitochondrial dysfunction and oxidative stress in Down syndrome. Mitochondria are the main sites of energy generation in cells. Down syndrome cells exhibit reduced mitochondrial activity, which ultimately contributes to a series of pathological changes, including increased generation of free radicals within cells and intracellular accumulation of Aβ. Oxidative stress and Aß production and accumulation are critically involved in Alzheimer’s disease pathogenesis. In addition, mitochondria play a critical role in cell death signaling pathways. Increased levels of free radicals as observed in Down syndrome lead to higher rates of mitochondrial DNA mutations, which can initiate programmed cell death, another important feature present in Alzheimer’s disease brains. Recent work from our laboratory indicates that reduced mitochondrial activity in Down syndrome is part of a cellular adaptation to prevent cellular damage by free radicals and to preserve basic cellular functions. Interestingly, down regulation of mitochondrial activity to prevent oxidative damage has been observed in several different organisms and cell types. Thus, strategies to protect mitochondria and block free radical production may be useful in both Down syndrome and Alzheimer’s disease.
To date, there is no cure for Down syndrome. Existing treatments are directed at alleviating or preventing clinical complications such as congenital heart defects or gastrointestinal blockage. Additionally, physical and speech therapy are available to further assist in improving quality of life for people with Down syndrome. Nutritional therapies have been used to enhance cognition although there is little data supporting their effectiveness. Antioxidants such as revastrol, celastrol, vitamins, and coenzyme Q10 are characterized by their ability to protect cells against oxidative damage through the clearance of free radical intermediates and by delaying the oxidation of cellular constituents. Antioxidants can improve the survival of Down syndrome neurons and prevent neuronal death, while improving spatial learning in a mouse model of Down syndrome. Given the genetic and phenotypic complexity underlying Down syndrome, specific therapeutic interventions have been limited. The significant increase in life expectancy that individuals with Down syndrome enjoy today must be complemented with effective treatments to enhance cognition and prevent age- and Alzheimer’s disease-related cognitive decline. Dendritic spine pathology has been associated with intellectual disability in Down syndrome and other neurological disorders, yet no therapeutic approach exists to prevent or restore spine structure and function. This is a promising area of research, which may pave the way for the discovery of new treatments to ameliorate neuronal connectivity and brain function in Down syndrome and other neurodevelopmental and neurodegenerative conditions.
Supported by the National Institute of Health, the Alzheimer’s Association and the State of California Department of Public Health Alzheimer’s disease initiative.