Brain Scientists Finally Discover the Glue that Makes Memories Stick for a Lifetime

Researchers discovered that a protein called KIBRA acts like a molecular "glue" in the brain. It sticks to another enzyme, PKMzeta, to make and keep connections between neurons strong—so memories last much longer.

Why It Matters

• Memory Stability: Without KIBRA, old memories fade when PKMzeta breaks down.

• Long-Term Recall: KIBRA holds PKMzeta in place, continually refreshing the "glue" that keeps synapses strong.

• Health Impact: Understanding this glue could lead to new treatments for Alzheimer's and other memory disorders.

How It Works

1. Synapse Tagging: When you form a memory, certain synapses "light up" and attract KIBRA.

2. Glue Action: PKMzeta binds to KIBRA at those tagged synapses, reinforcing them.

3. Perpetual Renewal: As proteins turn over, new PKMzeta keeps finding KIBRA, so the memory link stays intact for years.

Big Picture

• This solves a 40-year puzzle: how our brains keep memories despite constant protein turnover.

• It confirms Francis Crick's old "Theseus's Ship" idea—that you can replace parts over time and still remain the same whole.
• Scientists hope this insight will help design drugs or therapies that boost KIBRA–PKMzeta interactions, keeping our memories sharper as we age.

Research and therapeutic development efforts for KIBRA–PKMζ interactions:

CT-KIBRA Gene/Protein Therapy

• A study in the Journal of Clinical Investigation (JCI) reported that delivering the C-terminal fragment of KIBRA (CT-KIBRA) into the brains of transgenic mice expressing pathological tau restored synaptic plasticity and memory. CT-KIBRA stabilizes PKMζ levels, repairing long-term potentiation (LTP) and improving cognition even in the presence of ongoing tau toxicity .

Structural and Biochemical Target Identification

• A UK Research & Innovation project (UKRI BB/J008176/1) is using NMR spectroscopy, X-ray crystallography, and isothermal titration calorimetry to map the exact KIBRA–PKMζ binding interface. They are also screening small molecules and peptides that strengthen this interaction. These structural insights will guide the design of compounds that "stick" more tightly, boosting memory maintenance mechanisms .

Peptidomimetic Development

• An early patent (WO2013041239A1) describes peptide fragments based on the interaction surface between PKCζ (the isozyme of PKMζ) and KIBRA. These peptides serve as scaffolds to be optimized for prolonging PKMζ residency at synapses, thereby reinforcing the KIBRA–PKMζ "molecular glue" function .

Small-Molecule Screening and Lead Compounds

• While some molecules (e.g., zetastat, K-ZAP) have been described as inhibitors of KIBRA–PKMζ binding, the same platforms can be repurposed to find enhancers. High-throughput screening efforts are underway to identify small molecules that stabilize the KIBRA–PKMζ complex, with the goal of developing new drugs for memory disorders .

Next Steps
All of these approaches remain at the cellular or animal-model stage and have not yet entered human clinical trials. Future work will focus on optimizing brain delivery methods, assessing safety, and testing efficacy in Alzheimer's disease, other dementias, or post-traumatic stress disorder.

研究人員發現，一種名為 KIBRA 的蛋白質在大腦中就像分子「膠水」。它會黏附在另一種酶 PKMzeta 上，強化並維持神經元之間的連結，讓記憶持久保存。

為何重要

• 記憶穩定性：如果沒有 KIBRA，當 PKMzeta 被分解後，舊有記憶就會逐漸消失。

• 長期回憶：KIBRA 固定 PKMzeta 的位置，不斷重新補充這層「膠水」，保持突觸強度。

• 健康影響：了解這種「分子膠水」的機制，可能開發出治療阿茲海默症及其他記憶障礙的新方法。

作用機制

1. 突觸標記：形成記憶時，特定的突觸會被「點亮」，吸引 KIBRA。

2. 膠水作用：PKMzeta 附著在被標記的突觸上的 KIBRA，進一步加強連結。

3. 持續更新：隨著蛋白質不斷更新，新的 PKMzeta 持續找到 KIBRA，讓記憶連結得以維持數年。

整體意義

• 這項發現解開了歷時 40 年的謎題：蛋白質不斷替換，記憶卻能長存的原因。

• 也證實了 Francis Crick 所提出的「忒修斯之船」概念——即使部件持續更替，整體依然不變。
• 科學家希望，這項洞見能促使設計出增強 KIBRA–PKMzeta 互動的藥物或療法，隨著年齡增長也能保持記憶銳利。

以下是目前有關增強 KIBRA–PKMζ 相互作用的幾項研究與療法開發進展：

1. CT-KIBRA 基因／蛋白質療法

   • 美國《JCI》期刊報導，研究者利用 KIBRA 蛋白的 C 端片段（CT-KIBRA）在表達病理性 tau 的轉基因小鼠大腦中，成功恢復了突觸可塑性與記憶能力。CT-KIBRA 能穩定 PKMζ 水平，即使在 tau 毒性持續存在的情況下，也能修復長時程強化（LTP）並改善認知功能。

2. 結構與生化靶點鑑定

   • 英國科研項目（UKRI BB/J008176/1）正運用核磁共振、X 射線晶體學與熱量滴定等技術，精準解析 KIBRA 與 PKMζ 的結合界面，並篩選可增強該結合的小分子或肽類化合物。這些基礎數據將指導設計更牢固「黏附」的分子，以強化記憶維持機制。

3. 肽類模擬物研發

   • 早期專利（WO2013041239A1）描述了一系列基於 PKCζ（PKMζ 同系酶）與 KIBRA 互作界面的肽段。這些肽段可作為骨架，進一步優化以促進 PKMζ 在突觸中長時間駐留，從而加強 KIBRA–PKMζ 的「分子膠水」功能。

4. 小分子篩選與先導化合物

   • 雖已有針對抑制 KIBRA–PKMζ 結合的分子（如 zetastat、K-ZAP）被報導，但其技術路線同樣可逆向用於篩選增強相互作用的化合物。目前部分高通量篩選平台正積極尋找能穩定 KIBRA–PKMζ 複合物的小分子，以開發記憶障礙新藥。

下一步：上述策略多仍停留在細胞或動物模型階段，尚未進入人體臨床試驗。未來研究重點將放在優化這些分子或基因療法的腦內遞送方式、安全性評估，以及在阿茲海默症、其他失智症或創傷後壓力症候群等記憶相關疾病中的療效測試。