HTRA1 and brain disorders: A balancing act across neurodegeneration and repair.
Level 5 - mechanism / opinion, no new human data
Narrative review synthesizing mechanistic and preclinical literature without systematic search or original human data.
PubMed 41932381 · doi:10.1016/j.pneurobio.2026.102914
What was done
This narrative review summarizes literature regarding High temperature requirement protein A1 (HTRA1), a trypsin-like serine protease involved in proteostasis, extracellular matrix (ECM) remodeling, and cell signaling pathways (TGF-β, Wnt, Notch). The authors evaluate its regulatory functions across blood-brain barrier maintenance, tissue repair, inflammation, and its implicated roles in conditions such as CARASIL, cerebral small vessel disease, age-related macular degeneration, Alzheimer's disease, Parkinson's disease, and multiple sclerosis.
What was found
The abstract reports no quantitative metrics or effect estimates. It qualitatively describes HTRA1 as having a bidirectional role: decreased HTRA1 levels are linked to ECM accumulation and vascular fibrosis, whereas elevated HTRA1 activity promotes tissue breakdown, inflammation, and impaired repair. It also reviews HTRA1's biological interactions with ApoE, tau, lipid and cytoskeletal regulators, and endogenous inhibitors such as Macrophage Migration Inhibitory Factor.
Why it matters
Clarifying HTRA1's opposing pathological roles across neurodegenerative and neurovascular diseases highlights the need for targeted therapies that restore homeostatic balance rather than non-selectively inhibiting or overexpressing the protease.
Limits
The abstract describes a non-systematic narrative review providing no primary experimental or clinical trial data, sample sizes, or quantitative synthesis. Mechanistic associations derived across diverse conditions may not reflect uniform therapeutic targets in human clinical settings.
Cited by
- supports CARASIL is a genetic form of small vessel disease caused by HTRA1 mutations that exhibits white matter disease, microbleeds, lacunes, and blood-brain barrier dysfunction.