Neuropeptide Y Emerges as Both a Biomarker and Therapeutic Target Across Multiple Neurodegenerative Diseases | Research

The takeaway

Neuropeptide Y is dysregulated in Alzheimer's, Parkinson's, Huntington's, ALS, and retinal diseases, and its neuroprotective actions — reducing excitotoxicity, oxidative stress, and inflammation while promoting neurogenesis — make it a promising therapeutic target.

7+ diseases
Neurodegenerative conditions showing NPY dysregulation — from Alzheimer's to glaucoma — highlighting the peptide's central role in brain health

What the researchers found

The review synthesizes evidence showing NPY's dual role in neurodegeneration:

1. **As a biomarker**: NPY expression is altered in Alzheimer's, Parkinson's, Huntington's, ALS, Machado-Joseph disease, diabetic retinopathy, and glaucoma, potentially serving as a marker for disease progression.

2. **As a neuroprotective agent**: NPY alleviates excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while promoting neurogenesis, synaptic plasticity, and cellular resilience.

3. **Through specific signaling cascades**: NPY acts via PI3K/Akt, MAPK/ERK, and p38K pathways through its receptor subtypes to control cell survival, protein homeostasis (proteostasis), and inflammation.

Why it matters

Neurodegenerative diseases collectively affect tens of millions of people worldwide with limited treatment options. Finding that a single neuropeptide system is dysregulated across so many different conditions suggests a shared vulnerability that could be addressed therapeutically. NPY's neuroprotective actions through multiple independent mechanisms (anti-excitotoxic, antioxidant, anti-inflammatory, pro-neurogenic) make it an unusually versatile therapeutic target.

How the study worked

This is a narrative review compiling published evidence on neuropeptide Y's roles in neurodegeneration, covering its expression changes across multiple diseases and the molecular mechanisms underlying its neuroprotective effects.

What this study cannot tell us

This is a narrative review, not a systematic review, so coverage may be selective. Most of the neuroprotective evidence comes from cell culture and animal models, with limited human clinical data. The diversity of diseases covered is broad, which may obscure important disease-specific differences in NPY biology. Translating NPY-based therapies to clinical use faces challenges including blood-brain barrier delivery and potential metabolic side effects.

How to read the evidence

This is a narrative review synthesizing preclinical and clinical literature on NPY in neurodegeneration. While comprehensive, it does not present original data or use systematic review methodology.

When this study was published

Published in 2026, this is a current and comprehensive review capturing the latest understanding of NPY's roles in neurodegenerative diseases.

The bigger picture

Neuropeptide Y sits at the intersection of stress biology, metabolism, and neurodegeneration — connecting lifestyle and environmental factors to brain disease. The growing recognition that NPY has neuroprotective properties beyond its classical roles in appetite and stress adds it to the list of endogenous peptides being explored as therapeutic agents. The existence of multiple NPY receptor subtypes offers opportunities for selective drug development that targets specific protective pathways while minimizing side effects.

Questions still open

Which NPY receptor subtype is most critical for neuroprotection, and could subtype-selective agonists be developed as drugs?
Can NPY levels in blood or cerebrospinal fluid serve as reliable biomarkers for neurodegenerative disease progression?
How can NPY-based therapeutics be delivered across the blood-brain barrier effectively?

Common questions

What is neuropeptide Y and why is it important for the brain?

Neuropeptide Y (NPY) is one of the most abundant signaling peptides in the brain. It regulates stress responses, appetite, blood vessel tone, and immune function. Beyond these roles, NPY appears to actively protect brain cells from damage — reducing harmful overexcitation, fighting oxidative stress, calming inflammation, and even promoting the growth of new neurons. When NPY levels become disrupted, it may leave the brain more vulnerable to degeneration.

Could NPY become a treatment for Alzheimer's or Parkinson's disease?

It's a promising possibility but still in early research stages. NPY protects brain cells through multiple different mechanisms, which is encouraging because neurodegenerative diseases involve many types of damage. The main challenges are delivering NPY or NPY-like drugs into the brain (crossing the blood-brain barrier) and doing so without disrupting its other roles in appetite and stress regulation. Research into receptor-selective NPY drugs that target specific protective pathways is ongoing.

Read the original research

Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.

Neuropeptides, 115, 102583

View on PubMed ↗Publisher’s paper ↗

Citation

Palanivel, Viswanthram; Salkar, Akanksha; Shenoy, Avinash; Eva, Taslima Akter; Perera, Rumandee; Chitranshi, Nitin; Gupta, Veer; You, Yuyi; Mirzaei, Mehdi; Graham, Stuart L; Gupta, Vivek; Basavarajappa, Devaraj. (2026). Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.. Neuropeptides, 115, 102583. https://doi.org/10.1016/j.npep.2025.102583