Histochemistry of Alzheimer’ s Disease


Histochemistry of Alzheimer’s Disease

Introduction

Immunohistochemistry has played a central role in the developing of our understanding of Alzheimer’s Disease. This short article will review potential pitfalls and findings relating to amyloid and paired helical filament pathology.

Pitfalls

The relative insolubility of the abnormal proteins in Alzheimer’s Disease has made immunohistochemistry a valuable tool for studying the biochemistry of this condition. However, care must be taken in interpretation. Plagues and tangles, as well as neuronal cytoplasm, are ‘sticky’ and non-specific binding is easy to produce. Demonstration of an epitope does not demonstrate the protein. Multiple antibodies to different parts of the molecule should be used. Fixation often has unpreditable effects. Conformational differences between sections and blots may render Western Blot of limited value in some circumstances. Validation by Western is now almost obligatory however. Site of immunoreactivcity is not necessarily site of production (in situ hybridization an important parallel study to perform).

Immunohistochemistry for BA4 protein

a) Deposit types

Coronal Section of Brain in Normal and Alzhiemer's BrainsNumerous classifications have been presented. Simplest is into diffuse deposits, with little or no alteration of the general structure of the neuropil and plaques with amyloid deposition, with or without a distinct central core.

b) Deposit distribution

Deposits are not randomly distributed. Diffuse deposits are present in many more areas than are classical plaques. Some areas only ever show diffuse deposits (parvopyramidal layer of the presubiculum). Cored plaques are especially frequent in the calcarine cortex, CA4 subfield of the hippocampus and the amygdala.

c) Temporal sequence

From studies of Down’s syndrome, especially, it has become clear that diffuse deposits ‘mature’ into coarser deposits with increasing neuritic change. Such a sequence is not inevitable in all areas and it is not clear whether or not it is inevitable in all cases.

d) Relationship of deposits to other structures

Deposition of BA4 in blood vessels is important yet not fully understood. Earlier suggestions that plaques form in relation to blood vessels have not been borne out in studies of BA4 deposition. Positioning of glia seems to be secondary. PHF-bearing neurites occur more frequently in areas/cases where there is tangle formation. Dendritic association has been demonstrated in some areas.

Other plaque components

Although the impression is often given that BA4 is the only component of plaques many other proteins have been identified. (Serum amyloid P, complement components, alpha-antichymotrypsin, cholinesterase.) The significance of many of these observations is unclear. Immunohistochemistry is also of great value in demonstrating of cellular elements namely astrocytes and microglia.

Immunohistochemistry of tangles

a) Cytoskeletal components

Early observations were followed by similar studies demonstratng the presence of phosphorylated microtubule­ associated proteins, especially tau. Alz 50 immunoreactivity relates closely to that of abnormally phosphorylated tau and gives a much clearer background than other tau antibodies but is present in normal brain also. Similar immunoreactivity is reported in other PHF structures, namely neuropil threads and plaque neurites. Other MAPs have also been reported in tangles.

b) Other components

Tangles also stain for complement components, serum amyloid P, ubiquitin and rarely PGP 9.5. Sporadic reports describe immuno staining for parts of APP but a coherent picture has yet to emerge.

c) Extracellular tangles

Tangles in the extracellular space (presumably because their host cell has died), become immunoreactive for GFAP as astrocyte processes interleave between the bundles of PHF.They also adsorb proteins from the extracellular space including BA4 protein and bFGF.

Further Reading:

A) Full Text Papers:

1: Mastrangelo MA, Bowers WJ. Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer’s disease-related pathologies in
male triple-transgenic mice. BMC Neurosci. 2008 Aug 12;9:81.

2: Paulson JB, Ramsden M, Forster C, Sherman MA, McGowan E, Ashe KH. Amyloid plaque and neurofibrillary tangle pathology in a regulatable mouse model of
Alzheimer’s disease. Am J Pathol. 2008 Sep;173(3):762-72. Epub 2008 Jul 31.

3: Ikonomovic MD, Abrahamson EE, Uz T, Manev H, Dekosky ST. Increased 5-lipoxygenase immunoreactivity in the hippocampus of patients with Alzheimer’s
disease. J Histochem Cytochem. 2008 Dec;56(12):1065-73. Epub 2008 Aug 4.

4: Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H, Bugiani O, Del-Tredici K, Ferrer I, Gelpi E, Giaccone G, Graeber MB, Ince P, Kamphorst W,
King A, Korkolopoulou P, Kovács GG, Larionov S, Meyronet D, Monoranu C, Parchi P, Patsouris E, Roggendorf W, Seilhean D, Tagliavini F, Stadelmann C,
Streichenberger N, Thal DR, Wharton SB, Kretzschmar H. Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium.
Brain Pathol. 2008 Oct;18(4):484-96. Epub 2008 Mar 26.
5: Brion JP, Hanger DP, Bruce MT, Couck AM, Flament-Durand J, Anderton BH. Tau in Alzheimer neurofibrillary tangles. N- and C-terminal regions are differentially
associated with paired helical filaments and the location of a putative abnormal phosphorylation site. Biochem J. 1991 Jan 1;273(Pt 1):127-33.

6: Barton AJ, Harrison PJ, Najlerahim A, Heffernan J, McDonald B, Robinson JR, Davies DC, Harrison WJ, Mitra P, Hardy JA, et al. Increased tau messenger RNA in
Alzheimer’s disease hippocampus. Am J Pathol. 1990 Sep;137(3):497-502.

7: Galloway PG, Mulvihill P, Siedlak S, Mijares M, Kawai M, Padget H, Kim R, Perry G. Immunochemical demonstration of tropomyosin in the neurofibrillary
pathology of Alzheimer’s disease. Am J Pathol. 1990 Aug;137(2):291-300.

8: Spillantini MG, Goedert M, Jakes R, Klug A. Topographical relationship between beta-amyloid and tau protein epitopes in tangle-bearing cells in Alzheimer
disease. Proc Natl Acad Sci U S A. 1990 May;87(10):3952-6.

9: Joachim CL, Morris JH, Selkoe DJ. Diffuse senile plaques occur commonly in the cerebellum in Alzheimer’s disease. Am J Pathol. 1989 Aug;135(2):309-19.
10: Shin RW, Ogomori K, Kitamoto T, Tateishi J. Increased tau accumulation in senile plaques as a hallmark in Alzheimer’s disease. Am J Pathol. 1989
Jun;134(6):1365-71.

11: Dickson DW, Farlo J, Davies P, Crystal H, Fuld P, Yen SH. Alzheimer’s disease. A double-labeling immunohistochemical study of senile plaques. Am J
Pathol. 1988 Jul;132(1):86-101.

12: Perry G, Mulvihill P, Manetto V, Autilio-Gambetti L, Gambetti P. Immunocytochemical properties of Alzheimer straight filaments. J Neurosci. 1987
Nov;7(11):3736-8.

B) Books:

1. Histochemistry and immunohistochemistry of Alzheimer’s disease : Jürg Ulrich – 1993 – 63 pages

2. Excerpta medica: Neurology and neurosurgery: Volume 83 Excerpta Medica Foundation – 1989 -
3. Trends in Alzheimer’s disease research – Page 139 : Eileen M. Welsh – 2006 – 336 pages
4. Alzheimer’s disease: a century of scientific and clinical research – Page 57: George Perry – 2006 – 456 pages
5.Alterations in the Neuronal Cytoskeleton in Alzheimer’s Disease: Symposium on Reorganization of the Neuronal Cytoskeleton in Aging : Papers (Advances in Behavioral Biology):George Perry
5. Handbook of neuropsychology: Plasticity and rehabilitation – Page 703: François Boller,  Jordan Grafman – 2003 – 1026 pages -
6. Handbook of the neuroscience of aging – Page 395:Patrick R. Hof,  Charles V. Mobbs – 2009 – 690 pages

7. Cerebral amyloid angiopathy in Alzheimer’s disease and related disorders- Page 179 : Marcel M. Verbeek,  Harry V. Vinters,  Robert M. W. De Waal – 2000 – 357 pages
8. Neuroinflammatory mechanisms in Alzheimer’s disease- Page 47: Joseph Rogers,  Joseph Rogers (Ph.D.) – 2001 – 261 pages -