Rebecca Love

Untangling the relation between β-amyloid and tau

A years of debate over whether -amyloid or tau is the primary cause of Alzheimer’s disease (AD) pathology, scientists in the USA and Europe have proposed a link between these proteins. According to two papers published this week, the presence of -amyloid accelerates the formation of tau neurofibrillary tangles (NFTs) in transgenic mice. Jada Lewis and co-workers from the Mayo Clinic (Jacksonville, FL, USA) examined the distribution of NFTs and amyloid plaques in “double mutant” mice. The double mutants were created by crossing transgenic mice expressing a mutant form of amyloid precursor protein (APP), which leads to amyloid overproduction, with transgenic mice that form abnormal tau-containing NFTs (Science 2001; 293: 1487–91). “As expected, the tau/APP mice develop amyloid plaques and tangles but, more importantly, there is significantly enhanced neurofibrillary tangle pathology in the limbic regions of female mice”, says Michael Hutton, one of the investigators. “The tau/APP mice therefore provide evidence of an interaction between APP/A and the neurofibrillary tangle pathologies in AD.” The researchers also found that NFTs were not increased in the immediate vicinity of amyloid plaques, even in areas of the brain that displayed both types of lesion. Meanwhile, Jurgen Gotz (University of Zurich, Switzerland) and collaborators at Katholieke Universiteit Leuven (Belgium) provide supporting evidence for the interaction between -amyloid and tau. To determine whether -amyloid accelerates NFT formation, the researchers injected the fibrillar form of -amyloid peptide, A 42, into the somatosensory cortex and the hippocampus of mice expressing mutant human tau (Science 2001; 293: 1491–95). They observed five times more NFTs in A 42-injected animals than in animals injected with a control peptide. NFT formation was found in the amygdala, remote from the injection site in the hippocampus. “The anatomical separation of amyloid deposition and NFT formation is therefore consistent with A 42-induced axonal damage and, possibly, impaired axonal transport of tau”, the investigators conclude. Both research teams hope that the availablity of a transgenic model that replicates both amyloid and tau pathologies of AD will help in the search for more effective therapies. “These new results nicely link the two major neuropathological lesions of the disease in a temporal sequence”, comments Dennis Selkoe (Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA).

Memory loss independent of plaque formation in Alzheimer's model.

M overexpressing the human -amyloid precursor protein ( -APP) show signs of memory impairment in the absence of amyloid plaques, according to research published this week. “Since amyloid plaques do not develop in these mice, they are not requisite for an APPrelated cognitive dysfunction”, says Linda Higgins (Scios Inc, Sunnyvale, CA, USA), one of the investigators. Higgins and co-workers made transgenic mice expressing normal human -APP under the control of a neuron-specific enolase promoter. These mice do not exhibit amyloid plaque formation, but they do develop small, sparse, amyloid deposits in the hippocampus, amygdala, and cortex. They tested the transgenic mice, along with normal mice, in water maze tests and in “dry arena” tests specifically designed to test the animals’ spatial learning and memory functions in relation to cues in their environment. The researchers found that learning acquisition, processing, and recall of information in the water maze tests was impaired in an age-dependent manner in both normal and transgenic mice (Proc Natl Acad Sci 2001; 98: 14675–80). However, the transgenic mice did significantly worse than the normal mice as early as 3 months. This impairment was more marked at 6 months and 2 years. None of the mice exhibited cognitive deficits in the dry arena tests, which suggests that -APP o v e r e x p r e s s i o n elicits limited cognitive failure affecting some forms of spatial memory but not others. According to the investigators, this study demonstrates that plaque formation is not necessary for memory impairment in transgenic mice expressing human -APP. While plaques are diagnostic of Alzheimer’s disease (AD) the roles of soluble, intracellular, and plaque amyloid in the clinical presentation of AD are controversial. “It is reasonable to assume that any or all of these [forms] are capable of disrupting neural information processing sufficiently to impair learning and memory”, says David Morgan (University of South Florida, Tampa, FL, USA). “There is a growing body of evidence that the presence of -amyloid plaques is not a necessary causal factor underlying cognitive impairment in existing mouse models of AD”, comments Christopher Janus (University of Toronto, Toronto, Canada). “Future studies should throw more light on how this mouse model helps us understand the role of various forms of A in cognition and how relevant it is to modelling behaviour in AD”, he adds.

Stem-cell transplantation hope for Parkinson's disease treatment?

A could be triggered by the loss of a transcription factor involved in regulating the immune system, according to a report by US scientists this week. Laurie Glimcher (Harvard School of Public Health and Harvard Medical School, Boston, MA, USA) and colleagues report that people with asthma have less T-bet, a transcription factor that activates IFNin T-helper-1 cells (Th-1), in their lungs than non-asthmatic people. Furthermore, mice lacking the T-bet gene spontaneously developed signs of the disease. “These data show that T-bet regulates immune response in vivo and controls the Th-1/Th-2 cell balance, which is known to be important in asthma”, Glimcher told The Lancet. The researchers stained lung tissue sections from healthy people and seven patients with allergic asthma with a monoclonal antibody to T-bet and found lower levels of the protein in asthmatic patients. The result led the group to test whether lack of T-bet could trigger asthma. They looked for signs of the disease such as airway hyperresponsiveness (AHR), inflammation, and remodelling in mice with targeted deletions of the T-bet gene. Deletion mice showed increased AHR in response to challenge with the bronchial constrictor methacholine compared with normal mice. The T-bet deficient mice had also undergone airway remodelling and airway inflammation (Science 2002; 295: 336–38).