A hallmark of Alzheimer's disease is the presence in the brain of protein deposits, or plaques, which are thought to form over a long period. But studies in mice suggest that the plaques can grow overnight.
Alzheimer's disease is the commonest neurodegenerative disorder in ageing human populations. It is characterized by memory loss and behavioural alterations in its early stages, and by severe cognitive impairment and dementia later on. Alzheimer's is diagnosed definitively only after death, through the identification in the brain of extracellular protein deposits known as amyloid plaques and intracellular protein aggregates called neurofibrillary tangles. It is unclear exactly when and how the plaques form, but classical neuropathological studies have indicated that they develop over extended periods of time and long before the dementia becomes apparent. Reporting in this issue, however, Meyer-Luehmann et al. (page 720)1 provide surprising evidence that, in a mouse model of Alzheimer's disease studied in real time, amyloid plaques form extremely rapidly — within 24 hours.
Amyloid plaques form through the extracellular accumulation of polymers of the amyloid-β protein, which is a breakdown product of the amyloid precursor protein. Abnormal, tortuous neuronal processes surround the plaques, and an inflammatory reaction involving the brain's support cells, astroglia and microglia, further dramatizes the scene2.
To study the kinetics of plaque formation, Meyer-Luehmann et al. used state-of-the-art, multiphoton laser confocal microscopy, which is an innovative way to visualize tissues in vivo3. Compared with conventional microscopy tools, which have been used extensively to study amyloid plaques, the main advantage of the multiphoton technology is that it allows both optical sectioning of the tissue and deep visual penetration into it. Thus, without physically sectioning and chemically fixing a tissue, the investigator obtains three-dimensional, real-time information from an intact brain and, more importantly, a live animal.
Using this technique, the authors1 observed remarkably different kinetics of plaque formation from that expected: new plaques formed in only 24 hours, and their size and final characteristics stabilized within a week (Fig. 1). Stable plaques were also reported in an earlier study4 showing that, in another mouse model of Alzheimer's disease, reducing amyloid-β production might halt disease progression, although existing plaques persist.
A question that has long puzzled neuropathologists is how the initial lesion forms from which the plaques develop. Earlier studies5 involving conventional imaging of fixed tissues suggested that larger, diffuse or amorphous amyloid deposits might be the nidus for the mature plaques. But Meyer-Luehmann et al. describe a very different picture in which the mature plaques originate from smaller amyloid deposits (microplaques) that support a fast but eventually stable growth of the plaques. The origin of the microplaques is unclear, but it is possible that submicroscopic aggregates are present in the brain, perhaps related to the presence of small assemblies (oligomers) of amyloid-β molecules that may act as precursors to this rapid and sudden growth.
Among the features of the neurodegenerative process in Alzheimer's disease are damage to the synaptic connections between neurons, neuritic dystrophy — the formation of tortuous neuronal processes — and, eventually, loss of selective groups of neurons. Such damage to synapses and axons in specific neuronal populations has been strongly linked6,7 to the cognitive impairment seen in Alzheimer's disease. But the mechanism that causes the damage is a matter of great debate. One contentious suggestion8 is that synaptic damage is linked to the accumulation of neurotoxic amyloid-β oligomers rather than to that of the longer fibrils.
As clinical studies6,7 show that plaque abundance is a poor indicator of the severity of dementia, some investigators have questioned the pathogenicity of these lesions. But Meyer-Luehmann et al.1 show in mice that, in the early stages of the disease, microplaques can damage neighbouring axons and dendrites within days. This observation hints that the microplaques might interfere with the transport of organelles and molecules along the axon, perhaps resulting in neuritic dystrophy. Moreover, in the vicinity of the microplaques, amyloid-β oligomers might also contribute to neuritic dystrophy. Further studies are necessary to clarify the exact mechanisms behind the pathogenicity of the plaques, and the extent to which the associated neuritic dystrophy is linked to the dementia seen in Alzheimer's.
Meyer-Luehmann and colleagues' findings are limited to two animal models of the disease, and their validity should be verified in other models. Nonetheless, in their use of an innovative technique for studying lesions, the authors have opened a new avenue in neuropathology that can be extended to investigate the kinetics of other lesions (such as neurofibrillary tangles, the Lewy bodies in Parkinson's disease and the intranuclear inclusions in Huntington's disease), and to evaluate synaptic activity and response to treatment in living tissues.
Meyer-Luehmann, M. et al. Nature 451, 720–724 (2008).
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