Aging in Down Syndrome and the Development of Alzheimer's Disease Neuropathology

Abstract

Chromosome 21, triplicated in Down Syndrome, contains several genes that are thought to play a critical role in the development of AD neuropathology. The overexpression of the gene for the amyloid precursor protein (APP), on chromosome 21, leads to early onset beta-amyloid (Aβ) plaques in DS. In addition to Aβ accumulation, middle-aged people with DS develop neurofibrillary tangles, cerebrovascular pathology, white matter pathology, oxidative damage, neuroinflammation and neuron loss. There is also evidence of potential compensatory responses in DS that benefit the brain and delay the onset of dementia after there is sufficient neuropathology for a diagnosis of AD. This review describes some of the existing literature and also highlights gaps in our knowledge regarding AD neuropathology in DS. It will be critical in the future to develop networked brain banks with standardized collection procedures to fully characterize the regional and temporal pathological events associated with aging in DS. As more information is acquired regarding AD evolution in DS, there will be opportunities to develop interventions that are age-appropriate to delay AD in DS.

Figure 1

Aβ42 immunostaining in the frontal cortex of DS autopsy cases ranging in age from (A, B) 12 years, (C, D) 15 years, (E, F) 21 years and (G, H) 61 years. Note the extensive diffuse plaque deposition in younger cases compared with compared with cored and compacted plaques, subpial plaques and vascular amyloid in the older DS brain. (C42 pAb kindly provided by Dr. Takaomi Saido at the RIKEN Brain Institute, Japan and described in [38]). Plaques denoted by an asterisk at low magnification on the left (A, C, E, G) are shown at high magnification on the right (B, D, F, H). Scale bars, 100 microns.

Figure 2

Neuropathological features of DS brain. (A) Diffuse plaque labeling using an antibody against Aβ(R1282, gift from Dr. D. Selkoe, Boston, MA) in the temporal cortex of an individual with DS aged 21 years. (B) Significant cerebral amyloid angiopathy in a 46 year old male with DS and AD detected by immunostaining of the frontal cortex with Aβ1-40 antibody (arrows), which can be distinguished from extracellular plaques (arrowheads). (C) Neurofibrillary tangles labeled using the PHF-1 antibody (provided by Dr. Peter Davies- arrows) in the frontal cortex of a 46 year old male with DS and AD. (D) Immunostaining using IBA-1 for microglial cells shows significant hypertrophy (arrows) and association with the cerebrovasculature (arrowheads) suggesting neuroinflammation.