JOURNAL OF NEUROCHEMISTRY
| 2012 | 120 | 641–643
doi: 10.1111/j.1471-4159.2011.07574.x
*Robarts Research Institute, Department of Physiology and Pharmacology, Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
Read the full article ‘Exogenous seeding of cerebral b-amyloid deposition in bAPP-transgenic rats’ on page 660.
The increasing burden of Alzheimer’s disease (AD), caused by aging of the world’s population, has led many scientists and policy makers to suggest that AD will become one of the major causes of economic and health distress in the next few decades. Alzheimer’s disease predominantly affects episodic memory causing impaired cognitive function and eventually a loss of one’s identity. The pathological hallmarks of AD are extracellular plaques, formed by aggregation of amyloidb peptides (Ab) and other proteins, as well as intracellular neurofibrillary tangles, caused by Tau hyperphosphorylation. In addition to these pathological hallmarks, several lines of evidence indicate that soluble oligomeric forms of Abpeptides are likely to be one of the early toxic components in the disease. Albeit still under debate, many researchers accept the notion that increased levels of distinct forms of Ab oligomers trigger a cascade of pathological changes that culminates with cognitive deficits and ultimately to neuronal death (Ono and Yamada 2011). There are many aspects of the role of Ab peptides in Alzheimer’s disease that remain poorly understood. One subject on which we still have scarce knowledge is the relationship between distinct species of Ab oligomers and generation of amyloid plaques. Remarkably, synaptic activity seems to directly regulate the amount Ab peptides released into the interstitial fluid; long-term changes in neuronal activity can alter the levels of extracellular Ab and influence plaque deposition (Bero et al. 2011). These results agree with the proposal that a default mode network in the brain, defined by its functional connectivity during resting state, may be a key player in the cognitive and pathological dysfunction found in AD (Sperling et al. 2009). Indeed, the notion that Ab deposits may be related to the level of endogenous neuronal connectivity in the resting state is enticing. Importantly, plaques are dynamic entities able to
both capture aggregated forms of Ab as well as to free some previously captured soluble oligomers (Selkoe 2011). Unfortunately, little is known about the equilibrium dynamics of Ab deposits and its soluble forms. A number of experiments have recently uncovered novel aspects of the dynamic relationship between Ab and plaque formation and have done so by examining how Ab deposits can be seeded. A manuscript published in this issue of the Journal of Neurochemistry by Rebecca Rosen et al. (2011) has further advanced this concept. Thanks to the efforts of the Jucker and Walker laboratories, we now know that injecting diluted extracts from AD brains, or from old transgenic mice over-expressing APP with familial AD mutations, robustly accelerates plaque deposition in injected transgenic mice expressing mutated APP (Fig. 1, Meyer-Luehmann et al. 2006; Walker et al. 2006). Even peripheral inoculation of these Ab seeds has an effect on amyloid deposition (Eisele et al. 2010), suggesting that some sort of diffusible Ab could have an important role in plaque formation. However, most of this work has been done in transgenic mice that would eventually develop plaques when aged. Hence, whether plaque deposition is accelerated by these brain extracts, or there is de novo induction of plaque formation is still unknown. Rosen et al. (2011) have shed light on this process by performing brain extract injection experiments in a transgenic rat line that Received October 26, 2011; accepted October 31, 2011. Address correspondence and reprint requests to Marco A. M. Prado, Robarts Research Institute, Department of Physiology and Pharmacology, Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada. E-mail:
[email protected] Abbreviations used: AD, Alzheimer’s disease; TSE, transmissible spongiform encephalopathy.
Ó 2011 The Authors Journal of Neurochemistry Ó 2011 International Society for Neurochemistry, J. Neurochem. (2012) 120, 641–643
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642 | Review
Intrahippocampal infusion of AD tissue extract (seeding) to non-transgenic rats, control
Established models: e.g. APP23 transgenic mice
New model: homozygous APP21 transgenic rats
Seeding
Seeding
No plaque induction
Plaque formation in the absence of seeding
Plaque induction
No plaque induction
Plaque induction (9 months incubation period)
Old age
