This report includes information relevant to a potential model of cerebral amyloid angiopathy (CAA), APP-related; this disease is inherited as an autosomal dominant. The human gene implicated in this disease is APP, amyloid beta A4 precursor protein, which is the same gene implicated in Alzheimer disease 1 (see FBhh0000119); in many cases of Alzheimer disease symptoms of CAA are also present. Peptides derived from APP that aggregate into amyloid plaques also appear to be the pathogenic agent in CAA (Aβ40 as well as Aβ42). There is a single fly ortholog of APP, Dmel\Appl, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Appl is orthologous to two additional human genes, APLP1 and APLP2, neither of which is implicated in human disease.
A human disease model report has been created for this potential model because multiple variants of the human Hsap\APP gene associated with cerebral amyloid angiopathy have been introduced into flies and are available; however, they have not been characterized. Variant(s) implicated in human disease introduced (as transgenic human gene, APP): E693Q alone and E693Q double variant forms of the human gene have been introduced into flies. Variant(s) implicated in human disease introduced (as transgenic human amyloid peptide, Aβ42): D694N (D23N, Iowa type), E693Q (E22Q, Dutch type), and E693K (E22K, Italian type) have been introduced into flies. The variant E693G (E22G, Arctic type) is associated with both Alzheimer disease 1 and cerebral amyloid angiopathy; this variant has been characterized in flies in the context of an Alzheimer disease model (FBhh0000119).
Animals homozygous for a loss-of-function mutation in the Dmel\Appl gene exhibit learning and memory defects and neuroanatomy defective phenotypes. Physical interactions of the Dmel\Appl protein product have been described; see below and in the FlyBase gene report for Dmel\Appl. Phenotypic assays using the fly gene have allowed characterization of genetic interactions.
[updated Jun. 2017 by FlyBase; FBrf0222196]
Cerebral amyloid angiopathy (CAA), or cerebroarterial amyloidosis, refers to a pathologic process in which amyloid protein progressively deposits in cerebral blood vessel walls with subsequent degenerative vascular changes that usually result in spontaneous cerebral hemorrhage, recurrent headaches, ischemic lesions, hemorrhagic strokes, and progressive dementia (Revesz et al., 2003; pubmed: 14533778). [from MIM:605714; 2017.06.02]
Cerebral amyloid angiopathy (CAA) refers to the deposition of β-amyloid in the walls of the blood vessels of the central nervous system. It is a component of any disorder in which amyloid is deposited in the brain; it is not associated with systemic amyloidosis. While often asymptomatic, CAA may lead to dementia, intracranial hemorrhage, or transient neurologic events. [http://emedicine.medscape.com/article/1162720-overview, 2017.07.14]
[CEREBRAL AMYLOID ANGIOPATHY, APP-RELATED](https://omim.org/entry/605714)
[AMYLOID BETA A4 PRECURSOR PROTEIN; APP](https://omim.org/entry/104760)
In many cases of Alzheimer disease vascular amyloid deposits and other symptoms of CAA are observed (Ghiso, et al., 2014; pubmed:24670400).
APP-related CAA is the most common form of cerebral amyloid angiopathy (Revesz et al., 2009; pubmed:19225789). [from MIM:605714; 2017.06.02]
Amyloid-beta peptides derived from CAA-pathogenic APP variants aggregate and form plaques that accumulate in the blood vessels of the brain (Genetics Home Reference, APP gene; 2017.06.02).
Many to one: 3 human to 1 Drosophila. Three human genes, APP, APLP2 and APLP1, are orthologous to the fly gene Dmel\Appl.
Ortholog of human APP (reciprocal best hit), APLP2, and APLP1 (1 Drosophila to 3 human). Dmel\Appl shares 23-25% identity and 36-42% similarity with the 3 human genes.
