Molecular chaperons, amyloid and preamyloid lesions in the BRI2 gene‐related dementias: a morphological study

Abstract

Molecular chaperons or amyloid-associated proteins (AAPs) are deposited in vascular and parenchymal amyloid lesions in Alzheimer's disease (AD) and other amyloidoses. AAPs, such as apolipoprotein E (ApoE) or apolipoprotein J (ApoJ) have been strongly implicated in the pathogenesis of AD in vitro and in vivo. Furthermore the possession of the ApoE in4 allele is a well-studied risk factor for AD. In view of the similarities between AD and both familial British dementia (FBD) and familial Danish dementia (FDD), we investigated the presence of AAPs in these two diseases to understand better their role in the general process of amyloidogenesis. Immunohistochemistry for ApoE, ApoJ, serum amyloid P (SAP), alpha-1-antichymotrypsin, cystatin C, heparan sulphate proteoglycans, such as agrin, perlecan, syndecans, glypican-1 and for heparan sulphate glycosaminoglycan (HS GAG) side chains was carried out together with immunohistochemical preparations specific to the amyloid subunits. Significant or extensive staining for ApoE, ApoJ, agrin, glypican-1 and HS GAG side chains was found in both amyloid (fibrillar) and preamyloid (nonfibrillar) deposits in FBD and FDD. The remaining AAPs, including SAP, were predominantly found in amyloid lesions. Only very weak staining was present in a small proportion of the amyloid lesions using perlecan immunohistochemistry. These findings suggest that the deposition patterns of AAPs in FBD and FDD are mostly similar to those in AD. The presence of AAPs in the preamyloid lesions supports the notion that chaperon molecules may play a role in the early steps of fibrillogenesis.

Preferential association of serum amyloid P component with fibrillar deposits in familial British and Danish dementias: Similarities with Alzheimer's disease

“…Irrespective of their biochemical origin, amyloid deposits share tinctorial and morphological characteristics, among them the 6-8 nm twisted fibrillar structures that are birefringent under polarized light following Congo red staining and that show yellow-green fluorescence in ultraviolet light after exposure to thioflavin S. Also a common feature of all amyloid deposits is their association with a number of unrelated amyloid associated proteins. These molecules, including SAP, α1-antichimotrypsin, apolipoproteins E and J, glycosaminoglycans, interleukins, complement components and extracellular matrix proteins among others, are not a structural part of the fibrils although they colocalize with the deposits [33,[39][40][41][42]. Whether they Fig.…”

“…Aβ, ABri, and ADan amyloid immunoreactivity was assessed in paraffin embedded sections whereas SAP immunohistochemistry was performed in frozen sections. For paraffin embedded tissue, sections were deparaffinized in xylene, endogenous peroxidase was blocked with 0.3% H 2 O 2 in methanol, followed by formic acid and pressure cooker treatment as described [33]. Following blocking of non-specific binding with 10% non-fat milk in PBS, sections were subsequently incubated with the respective primary antibodies (Ab338, 1:2000; Ab5282, 1:1000; anti-Aβ, 1:4000) followed by either biotinylated anti-rabbit (Dako; 1:200) or anti-mouse (Dako; 1:200) and ABC (Dako).…”

Extracellular Chaperones and Amyloids

“…Much remains to be discovered, ensuring that exciting times lie ahead. , α2M (Fabrizi et al, 2001), Hp (Powers et al, 1981), SAP (Perlmutter et al, 1995) Spongiform encephalopathies Prion Protein Extracellular Clus (Chiesa et al, 1996;Freixes et al, 2004), α2M (Adler and Kryukov 2007), SAP (Ishii et al, 1984) Parkinson's disease α-synuclein Intracellular Clus , SAP (Kalaria and Grahovac 1990), α2M (Nicoletti et al, 2002) Dementia with lewy bodies α-synuclein Intracellular Clus , SAP (Kalaria and Grahovac 1990) , SAP (Rostagno et al, 2007) Familial Danish Dementia ADan Extracellular Clus (Lashley et al, 2006), SAP (Rostagno et al, 2007) Familial amyloid polyneuropathy TTR Extracellular Unknown…”

Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies

“…A constant feature of both FBD and FDD is that CAA is extensive and involves not only the blood vessels of the leptomeninges and cerebral cortex, but also of the white matter, deep grey nuclei, brainstem, cerebellum and spinal cord [47, 48, 100]. There is a wide range of amyloid-associated proteins in both ABri and ADan parenchymal lesions and CAA in a pattern similar to that seen in association with vascular and parenchymal Aβ deposits [61]. A marked astrocytic and activated microglial response together with complement activation of both the classical and alternative pathways have been documented in relation to ABri and ADan amyloid lesions, including CAA [47, 48, 62, 112].…”

“…A number of amyloid-associated proteins (AAPs) or ‘pathological chaperons’ co-deposit with different cerebral parenchymal and cerebrovascular amyloids. Such proteins are structurally and functionally diverse and their binding to the amyloid fibrils or their precursors may be additional factors influencing the formation of toxic misfolded proteins [34, 61]. …”