CD33 is a transmembrane receptor of the innate immune system that is expressed on the surface of peripheral monocytes and microglial cells in the brain. CD33 was first implicated in Alzheimer’s disease genetics in 2008, and in 2011 reached genome-wide significance in large GWAS in the U.S. and Europe. Since then, CD33 has been further validated in independent sample series in Canada, China, and elsewhere.

CD33 has primarily been studied in the peripheral immune system, where it inhibits proliferation of myeloid cells. More recent network analyses of gene expression patterns in the human brain placed CD33 inside an immune regulatory module together with other proteins relevant to AD, such as TREM2, TYROBP, and MSA4A. CD33 encodes a member of a superfamily called sialic acid-binding immunoglobulin-like lectins (Siglecs). In microglia, CD33 binds extracellular sialylated glycans on other cells or pathogens. Its cytoplasmic domain signals via phosphatidyl-inositol-3 kinase (PI3K) to dampen microglial phagocytosis; by comparison, TREM2 responds to ligand binding by activating PI3K to increase phagocytosis. In mouse models, CD33 has been shown to slow phagocytosis and Aβ clearance.

CD33 expression is elevated in AD brain and has been linked to both amyloid pathology and disease progression. The initial GWAS reported the C allele of the promoter polymorphism rs3865444 of CD33 as increasing AD risk. This SNP was subsequently associated with increased CD33 expression and microglial activation, and with diminished Aβ42 internalization and increased brain amyloid load. Subsequent research identified rs12459419, a protective variant in exon 2 of CD33. This SNP was reported to alter splicing of the CD33 mRNA such that the resulting protein lacks CD33’s sialic acid binding domain and therefore preserves the cell’s ability to take up and clear Aβ. The search for functional CD33 variants and their underlying mechanisms of action is an active area of research.

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Species: Mouse
Genes: APP, PSEN2
Modification: APP: Transgenic; PSEN2: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: Tg(Thy1-APPSwe)71Jgr x Tg(Prnp-PSEN2*N141I)30Jgr

Summary

Phenotype Characterization

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Species: Mouse
Genes: PSEN2
Modification: PSEN2: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: Tg(Prnp-PSEN2*N141I)30Jgr

Modification Details

Human PSEN2 gene with the N141I mutation driven by the mouse prion protein promoter.

Neuropathology

Unknown.

Cognition/Behavior

Unknown.

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Species: Mouse
Genes: APP, PSEN2
Modification: APP: Transgenic; PSEN2: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: Tg(Thy1-APPSwe,Prnp-PSEN2*N141I)152HLaoz

Summary

Phenotype Characterization

COMMENTS / QUESTIONS

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Progranulin burst on the scene of neurodegenerative disease as a major genetic cause of frontotemporal dementia (FTD) in 2006, only months before TDP-43 was identified as the main protein constituent of the histopathological lesions in the same patients. Up to that point, the only known FTD gene had been MAPT, located near the progranulin gene, GRN, on chromosome 17q21, and the twin discoveries broke a double logjam in the field. The roughly 70 GRN mutations known to date explain all 17q21-linked autosomal-dominant FTD families not accounted for by tau mutations, and because all FTD patients with a GRN mutation have TDP-43 pathology, TDP-43 explains these family’s tau-negative protein inclusions. GRN mutations explain up to 20 percent of familial and 5 percent of sporadic FTD. Histopathological commonalities notwithstanding, GRN mutations lead to a variety of clinical presentations, causing mostly behavioral FTD and progressive nonfluent aphasia, but also rare presentations of Alzheimer’s disease or parkinsonism. 

All pathologic GRN mutations reduce progranulin levels or result in loss of function. Indeed, blood progranulin levels indicate the presence of a pathogenic progranulin mutation and are rapidly becoming a diagnostic biomarker. Progranulin is a secreted growth factor known for its role in biological processes such as inflammation, wound healing, and cancer, and for its neurotrophic properties. It is proteolytically processed into peptides called granulins, which are poorly understood. Progranulin’s role in FTD is being investigated in parallel with potential therapeutic approaches aimed at increasing its levels in the CNS.

Several factors are known to influence progranulin expression. They include intrinsic factors, for example the gene TMEM106B and various microRNAs, as well as pharmacological agents, such as the histone deacetylase inhibitor SAHA and certain alkalizing drugs. Agents targeting the endocytic progranulin receptor sortilin-1 appear to increase plasma progranulin levels by slowing its internalization. Homozygous GRN mutations cause the rare lysosomal storage disease ceroid lipofuscinosis, and progranulin localizes to intraneuronal membrane compartments, including lysosomes. Both homozygous and heterozygous GRN knockout mice exist; the former show both behavioral and inflammatory phenotypes, the latter develop only the former.

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The most common mutation for familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is in the chromosome 9 open reading frame 72 gene (C9ORF72). Identified in 2011, this mutation takes the form of a repeat expansion of the six nucleotides GGGGCC. Healthy people have up to 30 repeats; mutation carriers can have hundreds, but repeat sizing methods are only semi-quantitative and repeat length has not been linked to clinical features. The expansion also explains a portion of sporadic cases. It shows signs of genetic anticipation, leading to earlier onset in successive generations.

C9ORF72 expansions vary tremendously in their clinical expression between and among affected families, causing amnestic and psychiatric symptoms in addition to the established features of FTD and ALS. Regardless of their clinical phenotype, C9ORF72 cases all have widespread TDP-43 neuropathology in brain areas that show atrophy and correspond to symptoms. Separately, C9ORF72 cases also feature TDP-43-negative inclusions made of aggregation-prone dipeptide repeats. These dipeptides are translated from the hexanucleotide repeats—which reside in non-coding introns—in an unusual, bidirectional manner previously described for the neurodegenerative disease spinocerebellar ataxia type 8. Dipeptide inclusions appear in different cells than TDP-43 inclusions, and they do not track with neurodegeneration.

The pathogenic mechanisms underlying C9ORF72-associated ALS/FTD are under intense study. Hypotheses include a lack of functional gene product, toxicity of the repeat dipeptides, and sequestration of critical RNA-binding proteins in RNA foci. C9ORF72 encodes an uncharacterized protein whose normal function is not understood. Several lines of induced pluripotent stem cells from C9ORF72 patients have been established, as well as a zebrafish model. Further animal models of C9ORF72 are being developed.

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