Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease

Abstract

Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer's disease. A fundamental tenet of the amyloid hypothesis of Alzheimer's disease is that the deposition of amyloid-β precedes and induces the neuronal abnormalities that underlie dementia 1 . This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques 2 . The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice 3 . Here we show that plaques form extraordinarily quickly, over 24 h. Within 1-2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.To explore the formation of amyloid plaques and to determine the effects of newly formed dense-cored plaques on the microarchitecture of the brain, we have developed a novel in vivo multiphoton imaging technique. This recognizes newly formed plaques and allows monitoring of their immediate vicinity thereafter to determine the rate of their formation and the temporal sequence of pathophysiological events. We imaged young (5-to 6-month-old) B6C3-YFP mice, an age when plaques begin to appear 4 (Fig. 1). We used three-colour imaging to establish fiduciary markers for repeated imaging: YFP positive neurons, dendrites and axons in the cortex, methoxy-XO4-labelled fibrillar amyloid-β deposits in the parenchyma and on vessel walls, and a fluorescent angiogram with Texas red dextran to image blood vessels. A volume of cortex (lamina I-III) that initially did not contain plaques was re-imaged until repeat imaging detected a new plaque, establishing its 'birthday'. To ensure that the appearance of a new plaque did not simply reflect a greater depth of imaging or a slightly different imaging volume, we went through each image stack and compared NIH Public Access Author ManuscriptNature. Author manuscript; available in PMC 2012 January 23. We postulated that we would occasionally observe the appearance and growth of new plaques within an imaging volume if the time interval between imaging sessions was long enough. From one weekly imaging session to the next, most of the sites remained unchanged ( Supplementary Fig. 1a-c). However, we identified 14 new plaques: instances in which a plaque appeared in a second imaging session in a volume that had clearly been unoccupied in the first images one week earlier (Fig. 1a-c).We examined the spatial relation between newly identified plaques and blood vessels. Measurements of the distance between vessel wall and the edge of a plaque confirmed that dense-core plaques develop...

The origin and development of plaques and phosphorylated tau are associated with axonopathy in Alzheimer’s disease

“…This is probably because these fibers arise from affected neurons, although we cannot exclude the possibility that this may be due to the neurotoxic effects of Aβ [6,24,34] . In another study, Meyer-Luehmann et al demonstrated in a mouse model of AD that plaques can grow overnight, with mature plaques originating from smaller amyloid deposits (microplaques) associated with alterations in neighboring neurites [35] . The origin of the microplaques is unclear, but our recent fi ndings suggest that they might be related to axonal leakage.…”

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease

“…Two models could be proposed. At one extreme, plaques could cause local damage to the neuropil as they deposit, but then remain relatively static lesions 10 as the disease pathologic process becomes increasingly dominated by nonplaque pathologies, including tau-associated lesions such as neuropil threads and tangles, neuronal and synaptic loss, and noneplaque-associated glial reactions. 5 At the other extreme, plaques could increasingly contribute to local neural system destruction over the entire course of the disease.…”

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

“…Alzheimer's disease (AD) is characterized by the progressive accumulation of extracellular amyloid  plaques, intracellular neurofibrillary tau, neuroinflammation, extensive neuronal cell death and dementia [126]. Increased expression of GRP78 was found in brain tissue of AD patients at the early pathological stage of AD compared to controls without dementia [127].…”