Brian H. Anderton

Dendritic changes in Alzheimer's disease and factors that may underlie these changes

It seems likely that the Alzheimer disease (AD)-related dendritic changes addressed in this article are induced by two principally different processes. One process is linked to the plastic response associated with deafferentation, that is, long-lasting transneuronally induced regressive changes in dendritic geometry and structure. The other process is associated with severe alterations of the dendritic- and perikaryal cytoskeleton as seen in neurons with the neurofibrillary pathology of AD, that is, the formation of paired helical filaments formed by hyperphosphorylated microtubule-associated protein tau. As the development of dendritic and cytoskeletal abnormalities are at least mediated by alterations in signal transduction, this article also reviews changes in signal pathways in AD. We also discuss transgenic approaches developed to model and understand cytoskeletal abnormalities.

Aluminium-induced tangles in cultured rat neurones. Enhanced effect of aluminium by addition of maltol.

SummaryNeurofilamentous tangles have been induced in cultured neurones from rat brain hemispheres by application of both aluminium and maltol. Quantitative evaluation revealed a significantly higher percentage of tangle containing neurones when using the aluminium-maltol mixture than after application of aluminium alone. Tangles were found to be consistently stained with monoclonal antibodies to neurofilament proteins but failed to react with polyclonal antibodies against microtubule-associated proteins 1, 2 and tau.

First one in, last one out: the role of GABAergic transmission in generation and degeneration

This paper is the result of discussions between scientists working in widely separated areas, united by an interest in the hippocampus. The discussions focused on the possible role of GABA in the development and maturation of the hippocampus and in neurodegeneration in Alzheimers disease (AD). GABA neurons are among the first to differentiate in the hippocampus and the properties of GABA neurotransmission in the developing hippocampus are distinct from those in the adult. GABAergic transmission may play a role in the clustering and maturation of GABA receptors, as well as of receptors for other neurotransmitters. The development and maturation of synaptic connections involves changes in the organization of the cytoskeleton, and mechanical force generation is probably required to establish appropriate points of contact. This generation of force may require coupling of specific receptors to the cytoskeleton through specialized proteins. In AD, much of the developmental process is progressively unraveled in the hippocampus, as afferent fibers, most notably from entorhinal excitatory neurons and from basal forebrain cholinergic cells, degenerate. This denervation undoubtedly has consequences for receptor systems, dendritic morphology and the underlying cytoskeleton. GABA neurons remain in the AD hippocampus, and may actually contribute to abnormal firing and degeneration of remaining pyramidal neurons. This attempt to bring together data from different areas of research has allowed the development of a scheme which identifies significant specific gaps in our knowledge, which could be readily filled by focused experimental work.

Neurofilaments from mammalian central and peripheral nerve share certain polypeptides

Preparations enriched in mammalian 10 nm frlaments, commonly referred to as neurofilaments have been made from peripheral nerve [I] and brain [Z-S]. Morphologically, isolated filaments from the two sources are indistinguishable and often appear aggregated [l-5] . However, there are considerable discrepancies between the reported polypeptide compositions of brain and peripheral nerve neurofilaments. Three polypeptides with mol. wt 200 000, 1.50 000 and 69 000 have been identi~ed as the major components of peripheral nerve neuro~laments [ I] . Indirect evidence obtained from studies of the slow component of axonal transport has also been used to implicate this same triplet of polypeptides in neurofilament structure [6,7] Preparations of brain 10 nm filaments contain a major polypeptide with a chain wt 50 000-60 000 which has been ascribed the brain neurofilament subunit [3-51, however it was noted that minor higher molecular weight polypeptides are usually present. The possible presence of glial 10 nm filaments in preparations from brain has been recognised for some time [3,8-lo] , however, the degree of any contamination by these filaments is difficult to assess since their constituent protein, glial fibrillary acidic protein, appears to comigrate electrophoretically with the major brain neurofilament polypeptide [4]. We have now directly compared the polypeptide composition of preparations enriched in

The isolation of brain 10 nm filament polypeptides from urea-extracts of brain white matter.

Until now it has been apparent that neurofilaments from the mammalian central and peripheral nervous systems are composed of different polypeptides. Brain neurofilaments have been reported to be composed principally of one polypeptide with a molecular weight in the region of 50 000 [l-4] whereas those of peripheral nerve have been found to contain a triplet of polypept~des with molecular weight of approximately 210 000, f 55 000 and 70 000 [5-73. We demonstrated that isolated brain 10 nm filaments contain minor components which corn&rate with peripheral nerve neurofilament polypeptides and that sciatic nerve does not contain a component corresponding to the major 50 000 mol. wt polypeptide of the preparations from brain [8]. We have also found that antisera to the 2 10 000 and 155 000 mol. wt polypeptides from brain specifically stain neurones of the cerebellum and sciatic nerve [9]. Thus it seems likely that neuro~lam~nts of central and peripheral neurones share these three po~y~ptides and that the 50 000 mol. wt material in preparations from brain may partially originate from glia [2,9&O]; a similar suggestion has now been made in [ 111. Because the recovery of protein is low (O.l-0.2%) for conventionally isolated brain 10 nm filaments and the contribution to the total protein of the 210 000, 1.55 000 and 70 000 mol. wt polypeptides is 2-S% for each f 121, we have developed an alternative and simple method for isolating these three components separately. We now describe this procedure which relies upon urea extraction of buffer-insoluble white matter, Since the urea changes the mobility of these

The Nature of Neurofibrillary Tangles

Dementia of the Alzheimer type (ATD), both presenile and senile, has a characteristic brain histopathology comprising neurofibrillary tangles (NFT), senile plaques, granulovacuolar bodies and Hirano bodies. Alzheimer-type NFT are also found in several other diseases, including Down’s syndrome, postencephalitic Parkinson’s disease, dementia pugilistica, subacute sclerosing panencephalitis, Parkinson-dementia complex and Hallevorden-Spatz syndrome (Wisniewski et al. 1979). In ATD, NFT are found in certain cortical and subcortical neuronal perikarya and consist of aggregates of abnormal fibres.