65 Cerebral amyloidosis, amyloid angiopathy, and their relationship to stroke and dementia ∗ Jorge Ghiso and Blas Frangione β-pleated sheet structure, the conformation responsi- Department of Pathology, New York University School ble for their physicochemical properties and tinctoreal of Medicine, New York, NY, USA characteristics. So far, 20 different proteins have been identified as subunits of amyloid fibrils [56,57,60 (for review and nomenclature)]. Although collectively they Cerebral amyloid angiopathy (CAA) is the common term are products of normal genes, several amyloid precur- used to define the deposition of amyloid in the walls of sors contain abnormal amino acid substitutions that can medium- and small-size leptomeningeal and cortical arteries, arterioles and, less frequently, capillaries and veins. CAA impose an unusual potential for self-aggregation. In- is an important cause of cerebral hemorrhages although it creased levels of amyloid precursors, either in the cir- may also lead to ischemic infarction and dementia. It is a culation or locally at sites of deposition, are usually the feature commonly associated with normal aging, Alzheimer result of overexpression, defective clearance, or both. disease (AD), Down syndrome (DS), and Sporadic Cerebral Of all the amyloid proteins identified, less than half are Amyloid Angiopathy. Familial conditions in which amyloid known to cause amyloid deposition in the central ner- is chiefly deposited as CAA include hereditary cerebral hem- vous system (CNS), which in turn results in cognitive orrhage with amyloidosis of Icelandic type (HCHWA-I), fa- decline, dementia, stroke, cerebellar and extrapyrami- milial CAA related to Aβ variants, including hereditary cere- dal signs, or a combination of them. bral hemorrhage with amyloidosis of Dutch origin (HCHWA- D), the transthyretin-related meningocerebrovascular amyloi- dosis of Hungarian and Ohio kindreds, the gelsolin-related 2. Aβ – related cerebral amyloidosis spinal and cerebral amyloid angiopathy, familial PrP-CAA, and the recently described chromosome 13 familial dementia in British and Danish kindreds. This review focuses on the Alzheimer’s disease (AD) is an age-dependent neu- various molecules and genetic variants that target the cere- rodegenerative disorder that causes a chronically pro- bral vessel walls producing clinical features related to stroke gressive decline in cognitive functions. The brains of and/or dementia, and discusses the potential role of amyloid patients suffering from AD are characterized by the in the mechanism of neurodegeneration. extracellular deposition of amyloid Aβ (Aβ) protein in plaques and cerebral blood vessels, the presence of intraneuronal neurofibrillary tangles (NFT) and reac- 1. Introduction tive gliosis, and the loss of presynaptic terminals and neuronal subpopulations in well defined brain areas. Amyloidosis is a disorder of protein conformation At autopsy, senile plaques and NFT chiefly define the leading to aggregation and fibrillization. A diverse disease whereas other pathological features are often group of proteins normally present in body fluids as ignored or regarded as coincidental findings. It is now soluble precursors can self-assemble into amyloid fib- becoming clear that a large majority of the patients rils and produce insoluble deposits in different tissues diagnosed with AD when examined at autopsy bear which may lead to cell damage, organ dysfunction and stroke-like lesions or infarctions, ranging from CAA, death. These fibrils, composed of low molecular weight degenerative microangiopathy compromising both the mass peptides (∼ 4 to 30 kDa), adopt a predominant endothelium and smooth muscle cells,cerebral infarcts, microinfarction, white matter changes related to small ∗ vessel disease and even hemorrhages [20,22,58]. Al- Correspondence to: Jorge Ghiso, Ph.D., Department of Pathol- though it is accepted that the presence of cerebrovas- ogy, New York University School of Medicine, 550 First Avenue, room TH-432, New York, NY 10016, USA. Tel.: +1 212 263 5775; cular disease or strokes may cause rapid cognitive de- Fax: +1 212 263 6751. cline and worsen the outcome in AD, it remains debat- Journal of Alzheimer’s Disease 3 (2001) 65–73 ISSN 1387-2877 / $8.00 2001, IOS Press. All rights reserved 66 J. Ghiso and B. Frangione / Cerebral amyloidosis, amyloid angiopathy, and their relationship to stroke and dementia able whether the vascular lesions are coincidental or sive amyloid deposition in the walls of leptomeningeal causal to the pathological processes. In sporadic AD, and cortical arteries and arterioles as well as in vessels wild type Aβ species, 39 to 43 residues in length, are in the brainstem and cerebellum. In addition to the the main constituents of the parenchymal and vascular vascular involvement, there is a moderate number of amyloid lesions and the inheritance of the apolipopro- parenchymal amyloid deposits resembling the diffuse tein E (apoE, chromosome 19) 4 allele is a prevailing plaques seen in Alzheimer disease. Dense plaque cores risk factor [31,40,49,61]. and neurofibrillary tangles are absent; cortical and hip- Mutations in the amyloid precursor protein (AβPP) pocampal neurons outside the infarcts appear to be well on chromosome 21 or presenilins (PS) 1 (chromo- preserved. Cerebral and cerebellar white matter show some 14) and 2 (chromosome 1) genes have been linked varying degrees of edema and myelin loss. The amy- to autosomal dominant forms of familial AD (FAD) loid subunit in HCHWA-D is homologous to Aβ; amy- (reviewed in [48]). As indicated in Fig. 1, multiple loid deposits are composed of a mixture of wild-type mutation sites either within or immediately outside the Aβ peptide and the Aβ-Q22 variant [41,54]. A single Aβ segment have been identified in the AβPP gene. nucleotide change (G for C) at codon 693 of AβPP [26] Surprisingly, AβPP mutations found outside the Aβ results in a single amino acid substitution (glutamine peptide are mainly associated with dementia whereas for glutamic acid) at position 22 of the Aβ peptide. those found inside the Aβ sequence result is stroke This was the first of a large series of mutations in the as the main clinical phenotype. These genetic vari- AβPP gene described in several kindreds with early on- ants are concentrated in the middle of the Aβ sequence set familial Alzheimer disease [48] (Fig. 1). Although (positions 21–22, corresponding to codons 692–693 the mechanism of fibril formation is not known, in vitro of AβPP) and are invariably associated with extensive studies [3,5,62] have shown that the Aβ-Q22 variant cerebrovascular pathology. The Flemish mutation A to forms fibrils at a more accelerated rate than wild-type G at codon 692), is the only variant so far described at Aβ. This increased amyloidogenic tendency is prob- position 21, resulting in an Ala to Gly substitution and ably due to a higher content of β-pleated sheet struc- a clinical phenotype of presenile dementia and cerebral ture and a conformational change in the middle part hemorrhage [19]. At position 22 of Aβ, three variants of the molecule induced by the disappearance of the have been described: i) the Arctic mutation (A to G negatively charged Glu side-chain in the mutant pep- at codon 693, resulting in the replacement of Glu for tide [9,45]. The presence of both allele products in the Gly), presenting as an early onset AD with prominent amyloid deposits suggest that the mutant peptide may vascular symptomathology [23], ii) the Dutch mutation induce a conformational change in the structure of the (G to C at codon 693, with the subsequent replacement normal Aβ peptide. Treatments to inhibit amyloidoge- of Glu for Gln), showing a phenotype predominantly nesis have been proposed [44,46]. associated to cerebral hemorrhage (see below) [26],and iii) the Italian mutation (G to A at codon 693, bearing Lys for Glu), presenting as a presenile dementia with 3. Cystatin C – related cerebral amyloid cerebral hemorrhage [51]. The deposition of these vas- angiopathy culotropic mutants in the cerebral vessel walls suggest alteration of the clearance-uptake mechanisms at the Hereditary cerebral hemorrhage with amyloidosis, blood-brain barrier. Icelandic type (HCHWA-I) is an autosomal dominant Of interest is the first mutation described in the disorder characterized by massive amyloid deposition AβPP gene linked to hereditary cerebral hemorrhage within small arteries and arterioles of leptomeninges, with amyloidosis, Dutch type (HCHWA-D), an auto- cerebral cortex, basal ganglia, brainstem and cerebel- somal dominant disease clinically defined by recurrent lum [16]. Although brain involvement is the main clini- strokes, vascular dementia and fatal cerebral bleeding copathological feature, silent amyloid deposits are also in the fifth to sixth decades of life [30]. Pedigrees present in peripheral tissues such as skin, lymph nodes, from the villages of Katwijk and Scheveningen have spleen, salivary glands, and seminal vesicles [2]. been described in The Netherlands [29]. Around two- Including information on progenitors born up to 200 thirds of the patients will die as a result of the first years ago, seven pedigrees have been described in small acute cerebral hemorrhage, while the rest will have sev- rural communities of West Iceland [21]. The main clin- eral minor stroke episodes leading to cognitive decline ical hallmark of the disease is cerebral hemorrhage with and dementia [18,59]. Histologically, there is a mas- fatal outcome in the third to fourth decade of life in J. Ghiso and B. Frangione / Cerebral amyloidosis, amyloid angiopathy, and their relationship to stroke and dementia 67 Stroke Dementia Dementia T H M V R D & Stroke F S 670 E 700 * *** 717 723 A G 680 ... E V KM D Y 28 K G A I I G L M V G G V V I A T V I V I T L V M L S 1 E N 40 42 I V G S .. E H G . H V Q D K E L 690 A V F F D N L V T I F G P QKG Dementia Schizophrenia Dementia Dementia Stroke Fig.