Hereditary and sporadic forms of abeta-cerebrovascular amyloidosis and relevant transgenic mouse models

Abstract

Cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils in the leptomeningeal and cerebral blood vessel walls, often causing secondary vascular degenerative changes. Although many kinds of peptides are known to be deposited as vascular amyloid, amyloid-beta (Abeta)-CAA is the most common type associated with normal aging, sporadic CAA, Alzheimer's disease (AD) and Down's syndrome. Moreover, Abeta-CAA is also associated with rare hereditary cerebrovascular amyloidosis due to mutations within the Abeta domain of the amyloid precursor protein (APP) such as Dutch and Flemish APP mutations. Genetics and clinicopathological studies on these familial diseases as well as sporadic conditions have already shown that CAA not only causes haemorrhagic and ischemic strokes, but also leads to progressive dementia. Transgenic mouse models based on familial AD mutations have also successfully reproduced many of the features found in human disease, providing us with important insights into the pathogenesis of CAA. Importantly, such studies have pointed out that specific vastopic Abeta variants or an unaltered Abeta42/Abeta40 ratio favor vascular Abeta deposition over parenchymal plaques, but higher than critical levels of Abeta40 are also observed to be anti-amyloidogenic. These data would be important in the development of therapies targeting amyloid in vessels.

Keywords: Alzheimer’s disease; CAA; amyloid β protein; cerebrovascular amyloidosis; dense-core plaques; pathogenesis; senile plaques; therapy; transgenic mice.

Figure 1.

Schematic representation of amyloid precursor protein (APP), positions of the Aβ sequence, transmembrane domain of APP (Tm), and sites of α-, β- and γ-secretase cleavage. NH₂ and COOH indicate the N-terminus and C-terminus of the protein. Aβ sequence is enlarged below. The constitutive proteolytic cleavage by α- and γ-secretases leads to the formation of the short p3 peptide and processing by β- and γ-secretases leads to Aβ40 and Aβ42 peptides with a consecutive release of a C-terminal APP intracytoplasmic domain (AICD). Also shown are AD/CAA-causing pathogenic amino acid substitutions within APP (see also Table 2 and visit www.molgen.ua.ac.be/ADMutations for a complete and updated list of these mutations).

Figure 2.

Spectrum of disease from primarily hereditary amyloidosis of Dutch and Flemish type to familial forms of Alzheimer’s disease (AD) and to mouse models of AD. The upper and middle panels depict Aβ staining with monoclonal antibody 4G8 in an HCHWA-D (E693Q) patient with CAA (a, e), a Flemish APP carrier with both CAA and senile plaques (b, f); a presenilin (PS)-1 L282V AD patient with senile plaques and prominent CAA (c, g), and Tg2576 mouse model with parenchymal plaques and CAA (d, h). The lower panel is phosphorylated tau staining (monoclonal antibody AT8) in temporal cortical regions of the same patients (i–k); or ubiquitin staining for Tg2576 (l). Note that HCHWA-D brains lacks dense-core senile plaque or phospho-tau pathology but do show diffuse amyloid plaques (e and i). Flemish APP and PS1 L282V carriers have phosphorylated tau immunostaining in neurofibrillary tangles, ballooned neurites and neuropil threads (j–k). Sections are immunostained with avidin-biotin complex/horseradish peroxidase system and color developed with 3’3’diaminobenzidine. Scale bars in a–d, 200 μm; and e–l, 20 μm.

Figure 3.

Physiological clearance and pathological deposition of Aβ in brain. (a) The newly synthesized Aβ is locally degraded by glial uptake and cell-associated and extracellular proteases or cleared along the periarterial interstitial fluid pathway or directly across the BBB through specific receptors or carrier-mediated mechanisms (EC, endothelial cell; SMC, smooth muscle cell). (b) At the level of BBB, Aβ is transported into the blood flow via a transcytosis mechanism mediated by LRP-1 and P glycoprotein transporters, in association with α2 macroglobulin and ApoE. A reverse transport from the blood towards the parenchyma is mediated by RAGE and LRP-2 receptors in association with apolipoprotein J. In addition, Aβ might be sequestered in the blood flow by immunoglobulins, ganglioside GM1, apolipoproteins, soluble RAGE receptors and gelsolin. (c) Astrocyte endfeet and pericytes also mediate Aβ intake by expressing LRP-1 and -2 receptors. As the production of Aβ exceeds its clearance, Aβ starts to deposit. It is possible that in situations of high Aβ42/Aβ40 ratio, highly fibrillogenic Aβ42 deposits near the site of production as diffuse plaques. It is also likely that such plaques sequester newly synthesized Aβ and mature to dense plaques. However, in situations where Aβ42/Aβ40 ratio remains unaltered or low, the major Aβ gradient is set towards vessels where Aβ42 seeds the deposition of more abundantly produced, and more diffusible, Aβ40 to form vessel-related CAA and dense plaques. Figure is not drawn to scale (adapted from Pirici et al., with permission from the publisher [118].