Editors' ChoiceAlzheimer’s Disease

Secreted frizzled-related protein 1 frazzles the brain in Alzheimer’s disease

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Science Translational Medicine  07 Aug 2019:
Vol. 11, Issue 504, eaay7697
DOI: 10.1126/scitranslmed.aay7697


Inhibition of ADAM10 α-secretase activity in neurons by secreted frizzled-related protein 1 may contribute to Alzheimer’s disease progression.

The most common form of dementia, Alzheimer’s disease (AD), is characterized by the accumulation of senile β-amyloid (Aβ) peptide plaques and intracellular neurofibrillary tangles. Genetic mutations in the amyloid precursor protein (APP), the precursor to Aβ peptide, can cause familial AD. Consequently, much research has focused on inhibiting Aβ production or eliminating plaque burden for therapeutic intervention.

In AD, the APP protein is sequentially cleaved by β-secretase, followed by γ-secretase cleavage, which generates the pathological Aβ peptide. Under normal conditions, the APP protein may be cleaved by the metalloprotease ADAM10 α-secretase, which releases a nonpathological extracellular sAPPα fragment that blocks the generation of Aβ. Mutations in the gene for ADAM10 that lower its activity promote the amyloidogenic pathway and are associated with late-onset AD. To further evaluate the role of ADAM10 α-secretase in AD, Esteve et al. measured its endogenous inhibitor the secreted frizzled-related protein 1 (SFRP1) in the brain and cerebrospinal fluid of patients with AD, revealing an enrichment in SFRP1 protein. The observed enrichment of SFRP1 protein suggested it potentially dampens ADAM10 α-secretase activity, thereby promoting Aβ production. SFRP1 protein was also elevated in the brains of aging APP/PS1 mice, a model for amyloidosis. Double RNAScope in situ hybridization revealed that SFRP1 was expressed in the cells of the choroid plexus and glial cells surrounding the plaques. Additionally, overexpressing SFRP1 advanced the plaque pathology, whereas homozygous knockout of the SFRP1 allele lowered plaque burden in APP/PS1 mice. To validate SFRP1 as a therapeutic target, the authors treated APP/PS1 mice prior to the onset of amyloid deposition with an anti-SFRP1 antibody and analyzed them five months later. Histopathological and electrophysiological analyses revealed neutralizing SFRP1 decreased plaque burden and blocked synaptic abnormalities in aged APP/PS1 mice.

The current study suggests neutralizing SFRP1 may potentially impede Aβ production by increasing ADAM10 α-secretase activity. A potential therapeutic approach is anti-SFRP1 antibody treatment demonstrated in a preventative study that delayed the development of amyloid-related pathologies in APP/PS1 mice. Future studies should evaluate if treating APP/PS1 mice with anti-SFRP1 antibody after disease onset also delays Aβ pathogenesis. The recent discouraging results of anti-Aβ immunotherapies in human clinical trials highlight the need for alternative immunotherapeutic targets.

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