Literature: A-K ; L-Z ; subject area
Compiled by: Julian Thorpe
Relationship of Plaques with Tangles
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Please Note: Due to time constraints, the text part of this page has not been updated for some time. However, references are added reasonably frequently. |
 | Extracellular deposits of beta-amyloid plaques
are - along with intracellular neurofibrillary
tangles (NFT)
- one of the two histopathological hallmark features of AD-affected
brain tissue. |
| Although the majority of research evidence appears to suggest
that deposition of (extracellular) beta-amyloid plaques precedes (intraneuronal)
tangle formation in AD-affected neocortical areas, there is still some
debate about how plaques and tangles interrelate. Many researchers hold the
view that fibrillar amyloid plaques are directly toxic to neurons and thereby
initiate a cascade of events leading to cytoskeletal disruption, tangle development,
loss of synapses and, ultimately, neuronal cell death and dementia. This
is the so-called ‘beta-amyloid cascade
theory’ of AD (Huse and Doms, 2001; Selkoe, 1999). However,
others dispute this notion of such a ‘linear’ chain of events as, for
example, tangles may occur in the absence of plaques in the class of neurodegenerative
diseases known as ‘tauopathies’ (Lee et al., 2001). Additionally,
some AD studies have revealed no correlation between these two lesions:
for example, a thorough systematic study of the olfactory bulb in AD and
normal brain yielded no correlation between A beta deposition and tangle
formation ( Kovacs et al., 1999). Furthermore, very recently, a view
has emerged that the neurotoxicity of A beta may be plaque-independent (
Haass and Steiner, 2001; Mucke et al., 2000; Nilsberth et
al., 2001 ), an observation which might serve to clarify this latter
dispute. Such studies indicate that AD is not always necessarily as linear
and uni-directional as the ‘cascade’ theory implies; future research on
the recently-discovered tau mutations (Crowther and Goedert, 2000
) should shed important new light on our understanding of the progression
of the disease. |
| Recent work on transgenic mice (summarised by Mudher and Lovestone, 2002) has taken us tantalisingly close to the answer to plaque/tangle inter-relationships. These authors report: |
 | the fact that (in human brain) "mutations in tau..." (that lead to the FTD disorders) "...give rise to tau-inclusion tangles but not plaques and yet mutations in APP or....presenilin ...give rise to both plaques and tangles almost proves that amyloid pathology occurs upstream of tau pathology " (my italics). |
| I am personally not quite convinced by this latter, but better evidence is... |
| that transgenic mice doubly mutant for mutant APP (the single transgene exhibits only plaques) and tau (the single transgene exhibits only tangles) have more tangles than mice with the single mutant tau transgene and tangles appear in areas of the brain that are unaffected in single mutant-tau transgenic mice (Lewis et al., 2001). |
| that amyloid injections also exacerbated tangle pathology in mutant-tau mice (Gotz et al., 2001). |
| that they suggest that "increasingly the finger points to souluble beta-amyloid as the culprit,.." |
| that it "remains a mystery" why beta-amyloid (injections) does not stimulate tau pathology with wild-type tau (Gotz et al., 2001) , yet other transgenic mice overexpressing wild-type tau exhibit tangles (Ishihara et al., 1999and 2001). |
| Rapoport et al. (2002) have shown that tau is essential for beta-amyloid toxicity. |
| References |
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