What have we learned so far?
Wilcock, D., Hurban, J., Helman, A., Sudduth, T., McCarty, K., Beckett, T., Ferrell, J., Murphy, M.P., Abner, E., Schmitt, F., Head., E. Down syndrome individuals with Alzheimer's disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer's disease. Neurobiol Aging, 2015, 1-7. Article in Press
Down syndrome (DS) is the most common genetic cause of intellectual disability and is primarily caused by the triplication of chromosome 21. The overexpression of amyloid precursor protein gene may be sufficient to drive Alzheimer's disease (AD) neuropathology that is observed in virtually all individuals with DS by the age of 40 years. There is relatively little information about inflammation in the DS brain and how the genetics of DS may alter inflammatory responses and modify the course of AD pathogenesis in this disorder. Using the macrophage classification system of M1, M2a, M2b, and M2c inflammatory phenotypes, we have shown that the early stages of AD are associated with a bias toward an M1 or M2a phenotype. In later stages of AD, markers of M1, M2a and M2c are elevated. We now report the inflammatory phenotype in a DS autopsy series to compare this with the progression in sporadic AD. Tissue from young DS cases (under 40 years of age, pre-AD) show a bias toward M1 and M2b states with little M2a or M2c observed. Older DS cases (over 40 with AD pathology) show a distinct bias toward an M2b phenotype. Importantly, this is distinct from sporadic AD where the M2b phenotype has been rarely, if ever observed in postmortem studies. Stimulated by immune complex activation of microglial cells and toll-like receptor activation, the M2b phenotype represents a unique neuroinflammatory state in diseased brain and may have significant implications for therapeutic intervention for persons with DS.
- Powell, D., Caban-Holt, A., Jicha, G., Robertson, W., Davis, R., Gold, B.T., Schmitt, F.A., Head, E. Frontal white matter integrity in adults with Down syndrome with and without dementia. Neurobiol Aging, 2014; 35(7):1562-1569.
To investigate the relationship between white matter (WM) integrity, thinking skills, and Down syndrome (DS) with and without Alzheimer's disease (AD), researchers looked at diffusion as a measure of brain integrity. Compared to the people without DS, DS participants had reduced integrity in their brain white matter (WM) connections, particularly in the frontal brain areas. Among DS participants, those with dementia exhibited much lower WM integrity than did those without dementia. This reduction in brain connections was also found to be related to less efficient thinking skills in participants with DS and AD. These observations support the theory that certain brain pathways in DS may be especially vulnerable to aging as well as AD. The results also suggest that this approach may be useful for research on AD in the general population.
- Head, E., Powell, D., Gold, B.T., Schmitt, F.A. Alzheimer's disease in Down syndrome. European Journal of Neurodegenerative Diseases (EJND), 2012; 1(3):353-364.
By 40 years of age, virtually every adult with Down syndrome (DS) has the senile plaque and neurofibrillary tangle pathology that is consistent with an Alzheimer's disease (AD) diagnosis. Existing research on adults with DS indicates that triplication of chromosome 21 leads to an overproduction of the beta-amyloid precursor protein that precedes extracelluar β-amyloid buildup. In addition, individuals with DS showed a higher level of oxidative stress, brain inflammation, brain glucose metabolism, and white matter degradation—all of these have been linked with AD. Despite developing the brain protein changes seen in AD, adults with DS typically have a delay of about 10 years in the onset of clinical dementia symptoms. It is also encouraging that some adults with DS appear to never develop these clinical symptoms. Thus, adults with DS represent a unique group of people to study prevention that targets age-linked brain pathologies before onset of clinical dementia.
- Cenini, G., Dowling, A.L., Beckett, T.L., Barone, E., Mancuso, C., Murphy, M.P., Levine, H. 3rd, Lott, I.T., Schmitt, F.A., Butterfield, D.A., Head, E. Association between frontal cortex oxidative damage and beta-amyloid as a function of age in Down syndrome. Biochim Biophys Acta. 2012; 1822(2): 130-138.
Beta-amyloid protein buildup in the front of the brain has long been thought to play a central role in the development of Alzheimer's disease (AD) pathology. To investigate potential associations between beta-amyloid protein accumulation and oxidative damage (from chemically reactive molecules containing oxygen, reactive oxygen species or ROS) in people with Down syndrome (DS), researchers compared autopsy tissues from DS donors with and without AD against those of control brain tissue donors. Elevated levels of oxidative, but not nitrosative damage (chemically reactive nitrogen containing molecules that can act together with ROS to damage cells), were seen in the frontal brain areas of individuals with DS. ROS further correlated with increased levels of a potentially neurotoxic form of amyloid-beta known as Aβ40. This unique correlation supports the hypothesis that lipid peroxidation (a form of oxidative stress that appears to occur at an early age in individuals with DS) may leave the brain more vulnerable to the effects of AD in DS.
- Di Domenico, F., Pupo, G., Tramutola, A., Giorgi, A., Schinina, M.E., Coccia, R., Head, E., Butterfield, D.A., Perlugi, M. Redox proteomics analysis of HNE-modified proteins in Down syndrome brain: clues for understanding the development of Alzheimer disease. Free Radic Biol Med. 2014; 71:270-280.
(Note: The proteome is defined as all of the proteins that are expressed by a genome, cell, tissue or organism at a given time. Redox Proteomics looks at the parts of the proteome that undergo reversible chemical reactions and those that are irreversible due to ROS.) In this study researchers analyzed these protein changes and ROS in the brain tissues of individuals with Down syndrome (DS) and Alzheimer's disease (AD). These tissues were then compared with younger and older people, and DS individuals (all without AD). In keeping with existing studies that show a strong link between ROS in the brain and neurodegeneration in DS, the redox proteomic analysis highlighted specific proteins in DS that are vulnerable to early damage and oxidative accumulation that might contribute to development of AD.
- Di Domenico, F., Coccia, R., Cocciolo, A., Murphy, M.P., Cenini, G., Head, E., Butterfield, D.A., Giorgi, A., Schinina, M.E., Mancuso, C., Cini, C., Perluigi, M. Impairment of proteostasis network in Down syndrome prior to the development of Alzheimer's disease neuropathology: Redox proteomics analysis of human brain. Biochim Biophys Acta. 2013;1832(8): 1249-1259.
Researchers used redox proteomics to investigate the effects of oxidative stress (ROS) on proteins in the frontal cortices of individuals with and without Down syndrome (DS). The investigation focused on DS individuals under the age of 40 to analyze potential ROS that might contribute to early neurodegeneration and AD onset. Proteomic analysis in pre-AD DS individuals indicated that oxidative damage targeted specific components of the brain's quality control system and a potentially harmful accumulation of protein aggregates is not only an early event in DS, but might contribute to neurodegeneration.
- Head, E., Doran, E., Nistor, M., Hill, M., Schmitt, F.A., Haier, R.J., Lott, I.T. Plasma amyloid-β as a function of age, level of intellectual disability, and presence of dementia in Down syndrome. J Alzheimers Dis. 2011; 23(3): 399-409.
This study analyzed the relationship between plasma amyloid-β, a protein contained in the senile plaques exhibited in Alzheimer's disease (AD) pathology, and cognitive function in individuals with Down syndrome (DS). Because the gene for amyloid-β precursor protein is encoded on chromosome 21—of which DS individuals have 3—DS individuals display elevated levels of amyloid-β protein. DS individuals are also at risk for developing AD. This study did not, however, find a correlation between increased plasma amyloid-β levels and presence of dementia. Non-demented DS individuals displayed significantly higher levels of plasma amyloid-β than did non-DS individuals with AD. Furthermore, AD and non-AD individuals with DS did not differ significantly in levels of plasma amyloid-β. Measurements of plasma amyloid-β were useful, however, in predicting cognitive function in adults with DS.
- Holler, C.J., Webb, R. L., Laux, A.L., Beckett, T.L., Niedowicz, D., M., Ahmed, R., R., Liu, Y., Simmons, C.R., Dowling, A.L., Spinelli, A., Khurgel, M., Estus, S., Head, E., Hersh, L.B., Murphy, M.P. BACE2 expression increases in human neurodegenerative disease. Am J Pathol. 2012; 180(1): 337-350.
The enzyme β-Secretase has been extensively studied for its role in cutting amyloid precursor protein to produce the amyloid-β peptide (peptides are amino acid building blocks for proteins) that eventually forms the brain plaques seen in Alzheimer's disease (AD). While much previous research illustrated increases in BACE (beta-site APP cleaving enzyme)1 as the more common of the two β-secretase enzymes in AD, this study examined BACE2. In an analysis of brain samples from patients with preclinical to late-stage AD, including people with Down syndrome and frontotemporal dementia, researchers found a strong associations between BACE1 and BACE2 levels. These findings suggest that both enzymes may be controlled by the same mechanisms, and that BACE2 should be further investigated for its potential role in neurologic disease progression.
- Martin, S.B., Dowling, A.L.S., Lianekhammy, J., Lott, I.T., Doran, E., Murphy, M.P., Beckett, T.L., Schmitt, F.A., Head, E. Synaptophysin and synaptojanin-1 in Down syndrome are differentially affected by Alzheimer's disease. J Alzheimers Dis. 2014;42(3):767-775.
Analysis of brain samples from individuals with sporadic Alzheimer's disease (AD) consistently documents synapse loss as a hallmark of AD progression (information from one neuron or nerve cell flows to another neuron across a synapse). These studies have also shown a reduction in synaptophysin (SYN), a glycoprotein located in presynaptic vesicles; occurring as well (vesicles are nerve cell structures that contain chemical signals or neurotransmitters). Little research has been done, however, to evaluate the age of onset of SYN protein loss relative to AD in individuals with Down syndrome (DS). An analysis of DS individuals with AD and those without shows that DS participants with AD had reduced levels of SYN, levels that compare to those seen in sporadic AD. In addition, SYN reduction was linked to reduced cognition. An increase in a different protein, synaptojanin-1, was observed in DS individuals and may be important in the evolution of cognitive dysfunction.
- Perluigi, M., Pupo, G., Tramutola, A., Cini, C., Coccia, R., Barone, E., Head, E., Butterfield, D.A., Di Domenico, F. Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain. Biochim Biophys Acta. 2014; 1842(7):1144-1153
Neuropathology consistent with an Alzheimer's disease (AD) diagnosis is seen in individuals with Down syndrome (DS) after the age of 40 years. To assess molecular mechanisms that lead to the development of dementia in DS, researchers compared the PI3K/Akt/mTOR axis (intracellular signaling pathway important in cellular regulation) in the frontal cortices of DS participants against those of age-matched controls. In both AD and non-AD DS individuals, hyperactivation of the PI3K/Akt/mTOR axis was observed. Such hyperactivation could affect key pathways involved in AD pathology, including amyloid beta deposition and tau phosphorylation.
- Hunter, M.P., Nelson, M., Kurzer, M., Wang, X., Kryscio, R.J., Head, E., Pinna, G., O'Bryan, J.P. Intersectin 1 contributes to phenotypes in vivo: implications for Down syndrome. Neuroreport. 2011;22(15): 767-772.
Levels of intersectin 1 (ITSN1), a gene that encodes a multi-domain scaffold protein involved in endocytosis (process by which cells absorb molecules) and signal transduction (cellular signaling), were elevated in the frontal cortices of individuals with Down syndrome (DS) under the age of 40. In DS individuals over the age of 40, however, ITSN1 levels were similar to non-DS controls. This association between the neurodegeneration observed at age 40 in DS individuals and the reduction in ITSN1 suggests that either neurodegeneration in older DS individuals causes a loss in ITSN1 expressing cells, or that earlier ITSN1 overexpression may promote neurodegeneration seen in DS.