Nicolás Achúcarro: A forgotten architect of glial biology and neuroprotection

Nicolás Achúcarro y Lund (1880–1918) was a pioneering neurohistologist whose brief but influential career helped shape the foundations of modern glial biology. Through innovative staining methods and insightful pathological observations, he revealed the structural diversity and reactivity of neuroglia at a time when these cells were largely regarded as passive support elements. His work anticipated several concepts that now occupy a central place in neuroscience, including neuroinflammation, glial metabolism, neurovascular interactions, and the contribution of glial cells to neurodegenerative disease. More than a century after his death, Achúcarro remains a foundational—yet often overlooked—figure whose legacy continues to inform contemporary research on neural resilience and neuroprotection.

Nicolás Achúcarro died at the age of 37. In that brief life, he helped transform neuroglia from a histological background into a biological problem. He did not name microglia. He did not formally define oligodendrocytes. Those discoveries are rightly attributed to his disciple Pío del Río‐Hortega. Yet without Achúcarro, neither conceptual nor technical conditions would have been in place for their emergence.

Achúcarro stands at a hinge point in the history of neuroscience: between Ramón y Cajal's neuron doctrine and the recognition that the “third element” of the nervous system was not inert scaffolding but a dynamic and reactive population of cells. His achievement was not simply methodological. It was epistemological. He altered what investigators were able—and willing—to see.

Trained in Madrid, Paris and Florence, and later in Munich under Emil Kraepelin and Alois Alzheimer, Achúcarro returned to Spain equipped with an unusual combination of clinical psychiatry and experimental neuropathology. ¹ , ² , ³ These formative years placed him within the intellectual networks that were reshaping the biological understanding of mental illness. In Paris, he encountered the neurological clinic model established by Charcot, where clinical observation was closely integrated with pathological anatomy. In Munich, he worked within the vibrant scientific environment created by Kraepelin and Alzheimer, where psychiatric disorders were increasingly investigated through microscopic examination of brain tissue.

Achúcarro, therefore, belonged to a generation of investigators attempting to reconcile psychiatry with cellular neuropathology. At the beginning of the twentieth century, intense debates revolved around whether mental illness could be traced to structural alterations in the nervous system. Histological investigation of the brain was thus not merely descriptive but explanatory—an attempt to anchor psychiatric disease within observable biological mechanisms.

His period in Washington at the Government Hospital for the Insane (St. Elizabeths Hospital) between 1908 and 1910 reinforced this orientation. There he organized one of the earliest laboratories dedicated to systematic neuropathological investigation within an American psychiatric institution and contributed to some of the earliest descriptions of Alzheimer‐type pathology reported in the United States. ² , ³

1. METHOD AND REVELATION

At the time Achúcarro began his investigations, neuroglia remained conceptually fragmented. Astrocytes were known but poorly distinguished morphologically. Rod cells observed in inflammatory conditions were enigmatic. The boundary between glial cells, connective tissue elements, and infiltrating immune cells remained blurred.

Achúcarro's 1911 tannin–ammoniacal silver method changed this landscape ⁴ (Figure 1). By refining silver impregnation techniques, he achieved improved visualization of glial processes and reticular structures. Cellular morphologies that had previously been indistinct suddenly appeared with remarkable clarity.

Figure 1.

From Achúcarro's reactive elements to the cellular definition of microglia and oligodendrocytes. (A) “Granuloadipose” cells, (B) “third element,” (C) microglia, and (D) oligodendrocytes. Reproduced from Ref. 5 under the terms of the Creative Commons Attribution License (CC BY) [5].

Histological technique in early twentieth‐century neuroscience functioned not merely as a technical tool but as an epistemic instrument. What could be seen determined what could be conceptualized. Golgi's silver impregnation method had revealed neurons; Cajal transformed that revelation into the neuron doctrine. Achúcarro extended this methodological lineage to glial biology.

Cells that had previously appeared amorphous now displayed elongated processes, rod‐like morphologies, and intricate relationships with blood vessels. Glial cells emerged as structurally diverse elements integrated within neural circuits and vascular interfaces. Achúcarro did not discover microglia, but he revealed the cellular heterogeneity that made their recognition possible. ⁶

Río‐Hortega's later silver carbonate method refined and extended these observations, ultimately distinguishing microglia and oligodendrocytes as distinct cellular populations.

2. GLIOARCHITECTONICS

Among Achúcarro's most forward‐looking works was his study of the cornu Ammonis and fascia dentata, a gliotectonic analysis of hippocampal cortex. ⁷ While cytoarchitectonics had become a standard method for studying cortical organization, glioarchitectonics remained largely unexplored.

Achúcarro examined cortical organization through the distribution and vascular relationships of glial elements. By mapping glial architecture across hippocampal subfields, he implicitly addressed questions that continue to occupy modern neuroscience: how glial cells contribute to circuit stability, metabolic support, and neuronal vulnerability.

Today, the hippocampus is recognized as a region of selective vulnerability in aging, epilepsy, and neurodegenerative disease. Microglial reactivity, astrocytic remodeling, oligodendrocyte dysfunction and neurovascular coupling are now recognized as central mechanisms underlying pathology in CA1–CA3 circuits and contribute substantially to age‐related cognitive decline and neurodegenerative disease. ⁸ , ⁹ , ¹⁰ , ¹¹ Achúcarro was already examining glial architecture across these subdivisions decades before the molecular era.

3. GLIAL REACTIVITY AND THE EARLY CONCEPT OF NEUROINFLAMMATION

Perhaps Achúcarro's most modern contribution lies in his interpretation of glial reactivity. ¹² In rabies, paralytic dementia, and senile pathology, he described morphological transformations of glial cells, including amoeboid forms, rod‐shaped cells, and perivascular proliferations.

Without the immunological vocabulary available today, Achúcarro nonetheless treated glial changes as active participants in disease processes. In contemporary terminology, these phenomena would correspond to microglial reactive states, astrocytic remodeling, and neurovascular interface dynamics. The conceptual seeds of neuroinflammation can therefore be recognized in his early descriptions.

4. GLIAL METABOLISM AND NEURAL RESILIENCE

Modern neuroscience increasingly recognizes that glial cells provide essential metabolic support to neurons. Astrocytes regulate glucose utilization and lactate shuttling, oligodendrocytes support axonal metabolism through myelin‐associated pathways, and microglia coordinate inflammatory responses that influence neuronal survival. Far from being passive support cells, glia are now viewed as active regulators of neural homeostasis, resilience, and repair.

Disruption of these systems contributes to the pathogenesis of numerous neurodegenerative disorders and has emerged as a major focus of contemporary neuroprotective research. ⁸ , ⁹ , ¹⁰ , ¹¹ Consequently, contemporary neuroprotective strategies increasingly focus on preserving or restoring glial homeostasis through modulation of neuroinflammatory responses, maintenance of astrocytic metabolic support, enhancement of oligodendrocyte survival, and promotion of myelin repair. Such approaches reflect a growing recognition that protecting neurons often requires protecting the glial networks that sustain them.

Although Achúcarro lacked the molecular tools required to identify these mechanisms, several of his observations pointed toward concepts that resonate strongly with modern views of neuroprotection. His descriptions of glial cells closely associated with blood vessels suggested an intimate relationship between glia and tissue metabolism, while his emphasis on the structural diversity and pathological transformation of glial elements implied specialized cellular functions within the nervous system. Most importantly, Achúcarro regarded glial alterations not as passive consequences of disease but as integral components of the pathological process itself.

Even though he could not have foreseen contemporary therapeutic approaches, Achúcarro's insistence that glial cells actively participate in both normal and pathological brain function anticipated a conceptual framework that underlies much of current neuroprotection research. In this sense, his work represents an early intellectual bridge between descriptive neuropathology and modern efforts to preserve neural function by targeting glial biology.

5. LEGACY

The creation of the Laboratory of Histopathology of the Nervous System under the Junta para Ampliación de Estudios institutionalized Achúcarro's vision. ¹³ Under his leadership trained Río‐Hortega and other investigators who would shape European neuropathology.

If Cajal established the neuronal doctrine, Achúcarro helped normalize the idea that glia deserved equal morphological rigor.

He reminds us that method precedes ontology; that glia are structurally heterogeneous; and that pathology is cellularly patterned rather than diffuse. ¹⁴ Modern single‐cell and spatial omics technologies now refine distinctions first stabilized by the morphological work of Achúcarro's generation.

Achúcarro occupies a paradoxical position in the history of neuroscience. He is both foundational and overshadowed. ¹⁵ His contribution was architectural: he constructed the scaffolding within which later discoveries became visible.

6. CONCLUDING REMARKS

Modern neuroscience increasingly acknowledges that understanding brain function and dysfunction requires understanding glia. In that sense, Achúcarro was not merely a historical precursor. He was an early architect of a paradigm that continues to unfold today, one in which glial biology lies at the center of neurodegeneration, neural resilience, and neuroprotection.

AUTHOR CONTRIBUTIONS

Carlos Matute: conceptualization; investigation; writing – original draft; writing – review and editing. Luis Pacheco: Investigation; historical research; writing – review and editing.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

Not applicable. This article is a historical commentary and does not involve human participants, animals, or identifiable personal data.

Matute C, Pacheco L. Nicolás Achúcarro: a forgotten architect of glial biology and neuroprotection. Neuroprotection. 2026;1‐4. 10.1002/nep3.70051

DATA AVAILABILITY STATEMENT

All data and materials supporting the findings of this study are incorporated within the article.