What is Dr. Zubair Khalid's research focus?

Dr. Zubair Khalid specializes in molecular virology, mRNA vaccine development, and computational biology, with a focus on avian pathogens like IBDV and Avian Reovirus.

Where is Dr. Zubair Khalid currently working?

Dr. Zubair Khalid is a Postdoctoral Research Associate at the University of Maryland (UMD), specifically within the Department of Animal and Avian Sciences.

Bovine Spongiform Encephalopathy: Mad Cow Disease

Name: Bovine Spongiform Encephalopathy: Mad Cow Disease
Creator: Dr. Zubair Khalid

By Dr. Zubair Khalid, DVM, MS, PhD · 2026-09-20

Bovine spongiform encephalopathy (BSE), widely known as mad cow disease, is a fatal neurodegenerative disease of cattle caused by a misfolded form of the prion protein. The misfolded protein, called PrPSc, converts the normal cellular prion protein (PrPC) into more copies of itself, producing microscopic holes in the brain without any inflammatory response.

BSE belongs to the transmissible spongiform encephalopathies, a family of diseases that includes scrapie in sheep and Creutzfeldt-Jakob disease (CJD) in humans. The human form linked to BSE is variant CJD (vCJD) [1]. This article explains what mad cow disease is, how the prion mechanism works, what the symptoms of mad cow disease look like in cattle, how it spreads, and how surveillance and feed controls have reshaped the disease.

This article is educational and is not a substitute for veterinary diagnosis or treatment.

What Is Mad Cow Disease?

BSE is a chronic, progressive, and always fatal disease affecting the central nervous system of cattle. It was first identified in the United Kingdom in 1986 [1]. The disease is caused by a misfolded isoform of the prion protein, a glycoprotein expressed widely throughout the body but found at highest concentration in neurons [1].

The term "spongiform" describes the hallmark microscopic lesion. Affected brain tissue develops vacuoles, which are small fluid-filled spaces within and between neurons. Under a microscope, this gives the tissue a sponge-like appearance. The term "encephalopathy" means disease of the brain. Together, spongiform encephalopathy describes the defining pathology.

BSE is not caused by a bacterium, virus, fungus, or parasite. It is caused by a protein that has adopted an abnormal shape. This is why standard antimicrobial treatments and standard sterilization methods are ineffective, and why the disease behaves differently from conventional infections.

The Prion Mechanism

Normal Prion Protein

PrPC is a normal host protein encoded by the PRNP gene. It is anchored to the outer surface of cell membranes and is expressed most abundantly in the brain. Its precise physiological function remains under investigation, but it appears to participate in copper binding and cellular signaling [2]. The protein contains a region called the octapeptide repeats, a highly conserved structural feature that plays a critical role in prion misfolding and neurotoxicity [3].

Conversion to PrPSc

Prion disease begins when PrPC changes shape into the disease-associated isoform, PrPSc. The "Sc" stands for scrapie, reflecting the first prion disease identified. PrPSc is rich in beta-sheet structure, whereas PrPC is predominantly alpha-helical. This conformational shift makes PrPSc resistant to proteases, heat, and conventional decontamination [4].

Once PrPSc forms, it acts as a template. It binds to normal PrPC and induces the same misfolding, creating a self-propagating chain reaction. The misfolded protein accumulates in the brain, disrupts neuronal function, and eventually kills neurons. The brain responds with reactive changes but not with inflammation, because the immune system does not recognize PrPSc as foreign. This absence of inflammation is a key distinguishing feature of prion diseases.

The Spongiform Lesion

As neurons die, the brain tissue develops the characteristic vacuolation. The distribution of these vacuoles varies by prion strain. In classical BSE, the brainstem, particularly the obex region, is heavily affected [5]. In atypical forms, the distribution shifts toward cortical or cerebellar regions [5].

flowchart TD
    A[Normal prion protein PrPC] --> B[Misfolded PrPSc appears]
    B --> C[PrPSc binds PrPC]
    C --> D[PrPC converts to PrPSc]
    D --> E[Misfolded protein accumulates]
    E --> F[Neurons lose function]
    F --> G[Spongiform vacuolation]
    G --> H[Clinical signs appear]
    H --> I[Progressive decline]
    I --> J[Death]

Classical BSE Versus Atypical BSE

BSE is not a single entity. It is a spectrum of strain-defined prion disorders, each with distinct origins, neuroanatomical trajectories, and surveillance implications [5].

Classical BSE

Classical BSE (C-BSE) is the form responsible for the major epidemic in the United Kingdom and the linked cases of vCJD in humans [6]. The primary risk factor is feed containing contaminated meat-and-bone meal (MBM), a protein supplement made from rendered ruminant tissues [1]. When cattle consumed MBM produced from infected animals, the prions entered the food chain and established new infections.

Classical BSE typically targets the brainstem, with prominent involvement of the obex. Lymphoid tissue involvement is more consistent in classical BSE than in atypical forms, which affects diagnostic strategies [5].

Atypical H-Type and L-Type BSE

Atypical BSE cases are classified by the molecular weight of the protease-resistant prion fragment. H-type BSE produces a higher molecular weight fragment, and L-type produces a lower molecular weight fragment. These forms are believed to arise spontaneously rather than through feed contamination, though genetic factors can influence susceptibility.

A 2021 H-type BSE case in Canada was associated with a novel E211K polymorphism in the PRNP gene, confirmed as a germline mutation. This was the first Canadian BSE case with this predisposing mutation [7]. In that case, PrPSc was restricted mainly to the central nervous system, with no or only weak involvement of peripheral tissues [7].

The zoonotic potential of atypical BSE differs from classical BSE. L-type BSE prions have transmitted to cynomolgus macaques by intracranial challenge, suggesting possible zoonotic potential [6][8]. However, H-type BSE prions did not transmit to cynomolgus monkeys after intracranial or oral challenge, and no PrPSc was detected in brain, peripheral neurons, or lymphatic tissues [9]. These findings indicate a substantial barrier against H-type BSE transmission to humans [9].

Transmission Routes

Feedborne Transmission

The dominant route of classical BSE transmission is oral exposure through contaminated feed. The MBM produced from infected cattle contained prions that survived rendering. Calves and adult cattle that consumed this material became infected. This feedborne cycle drove the epidemic [1].

Maternal and Horizontal Transmission

Maternal transmission from dam to calf has been investigated but is considered a minor route compared with feed. Horizontal transmission between adult cattle is not a significant feature of BSE epidemiology. The disease does not spread through direct contact, respiratory droplets, or environmental contamination in the way that conventional infectious diseases do.

Cross-Species Transmission

BSE has been confirmed naturally in goats, raising concern about possible entry into the food chain through small ruminants [10]. Experimental studies have shown that sheep with the ARR/ARR genotype, normally considered resistant to classical scrapie, can still develop prion disease after oral challenge with ovine-passaged classical BSE, though incubation times are markedly longer (approximately 50 months) compared with ARQ/ARQ sheep (approximately 20 months) [11]. Passage through ARR/ARR sheep did not increase the agent's zoonotic potential [11].

Symptoms of Mad Cow Disease in Cattle

The clinical signs of BSE in cattle are behavioral, neurological, and nonspecific. They typically appear in animals between 4 and 6 years of age, reflecting the long incubation period. The signs progress over weeks to months and always end in death.

Behavioral Changes

Early signs include nervousness, agitation, and aggression [1]. Affected cattle may become difficult to handle and may react excessively to noise, touch, or sudden movement. This hyperesthesia, or increased sensitivity to stimuli, is a classic feature. Some animals become withdrawn and depressed rather than agitated.

Neurological Signs

Ataxia, or incoordination, is common. Cattle may have difficulty standing, may sway, or may show an irregular body posture [1]. Fine tremors may be visible, particularly when the animal is stressed or excited. Some cattle develop a stiff, stilted gait.

Physical Decline

Weight loss occurs despite continued appetite. Milk yield decreases in lactating cows. Body condition deteriorates as the disease progresses. These signs reflect the underlying neurodegeneration and the animal's inability to maintain normal function.

Progression and Death

There is no treatment for BSE. The disease is invariably fatal. Affected cattle are typically euthanized on humane grounds once a diagnosis is suspected or confirmed. The interval from first clinical signs to death or euthanasia is usually weeks to a few months.

Diagnosis and Surveillance

Clinical Suspicion

BSE cannot be reliably diagnosed on clinical signs alone. The signs overlap with other neurological conditions, including listeriosis, rabies, and nervous ketosis. Any adult cow showing progressive neurological signs should be reported to veterinary authorities for investigation.

Postmortem Diagnosis

Definitive diagnosis requires examination of brain tissue. The obex, a region at the base of the brainstem, is the preferred sampling site for classical BSE [5]. Histopathology reveals spongiform vacuolation. Immunohistochemistry detects PrPSc accumulation. Western blotting identifies the protease-resistant prion protein and can distinguish classical from atypical forms.

Antemortem Testing

Screening living animals for BSE is challenging [1]. No practical blood test exists for routine field use. Research tools such as real-time quaking-induced conversion (RT-QuIC) can detect prions with high sensitivity in brain homogenates, but these are laboratory methods, not point-of-care tests [12].

Active Surveillance

Active surveillance programs test cattle that die on farm, are euthanized, or show neurological signs. These programs are designed to detect BSE cases that would otherwise go unnoticed. Surveillance design must account for differences in tissue distribution between classical and atypical BSE, since atypical cases may have little or no peripheral involvement [5][7].

Control Measures

Feed Ban

The feed ban is the cornerstone of BSE control. Prohibiting the feeding of ruminant-derived protein to ruminant animals breaks the feedborne cycle [1]. The ban on meat-and-bone meal in cattle feed was implemented in the United Kingdom and later adopted in many countries. This measure dramatically reduced the incidence of classical BSE.

Specified Risk Material Removal

Specified risk materials (SRMs) are tissues that carry the highest concentration of BSE infectivity. In cattle, these include the brain, spinal cord, eyes, and certain lymphoid tissues. Removing these materials from the food chain prevents human exposure. The removal of SRMs remains essential even in countries with low BSE prevalence [11].

Active Surveillance Programs

Surveillance programs test target populations of cattle to detect BSE and monitor the effectiveness of control measures. These programs must be designed to detect both classical and atypical forms, which may require different sampling strategies [5].

Genetic Selection

Genetic factors influence BSE susceptibility. Polymorphisms in the PRNP gene, including single nucleotide polymorphisms and insertion/deletion variants, have been associated with susceptibility in various cattle breeds [13][14][15]. Selective breeding for resistance-associated alleles has been proposed as a complementary control strategy, though it does not replace feed bans and SRM removal.

Decontamination

Prions are unusually resistant to inactivation [4]. Standard autoclaving at 121 degrees Celsius or 134 degrees Celsius may not fully inactivate BSE agents on contaminated surfaces. Sodium hydroxide (2N NaOH) is used in some protocols, often combined with autoclaving, to decontaminate instruments and surfaces [4]. These measures are relevant in laboratory and surgical settings where prion-contaminated material may be present.

Comparison of BSE, Scrapie, and vCJD

Feature	Classical BSE	Scrapie	Variant CJD
Host	Cattle	Sheep and goats	Humans
Cause	Misfolded PrPSc	Misfolded PrPSc	Misfolded PrPSc
Primary transmission	Contaminated feed (MBM)	Oral, environmental, maternal	Consumption of BSE-contaminated beef
Incubation period	4 to 6 years typically	2 to 5 years	Years to decades
Key clinical signs	Nervousness, ataxia, hyperesthesia, weight loss, decreased milk yield	Scratching, incoordination, wasting	Psychiatric signs, ataxia, myoclonus, dementia
Lymphoid involvement	Present in classical BSE	Prominent	Present
Zoonotic potential	Yes (causes vCJD)	Not linked to human disease	N/A (human disease)

Human Counterpart: Variant CJD

Variant Creutzfeldt-Jakob disease (vCJD) is the human prion disease linked to BSE. Strong evidence connects BSE to human transmission through consumption of contaminated beef products [1]. The disease was first recognized in the United Kingdom in the 1990s, following the BSE epidemic in cattle.

vCJD differs from classical CJD in several ways. It affects younger people, with a median age at onset in the late 20s. Early symptoms are often psychiatric, including depression, anxiety, and withdrawal. Neurological signs follow, including ataxia, involuntary movements, and progressive cognitive decline. The disease is always fatal.

The link between BSE and vCJD led to stringent control measures in many countries, including feed bans, SRM removal, and surveillance programs. These measures have reduced the incidence of both BSE and vCJD, but the long incubation period of prion diseases means that new cases may still appear decades after exposure.

Clinical Relevance, Limitations and Common Mistakes

Clinical Relevance for Veterinarians

BSE is a notifiable disease in most countries. Any cattle showing progressive neurological signs should be reported to the appropriate veterinary authority. The differential diagnosis includes listeriosis, rabies, nervous ketosis, hypomagnesemia, and other neurological conditions. Definitive diagnosis requires postmortem brain examination.

Limitations of Current Knowledge

The precise function of PrPC remains under investigation. The factors that trigger the initial misfolding event in spontaneous atypical BSE are not fully understood. The zoonotic potential of L-type BSE is supported by experimental transmission to macaques, but human cases have not been reported [6][8]. The long-term effectiveness of genetic selection for BSE resistance in cattle is still being evaluated.

Common Mistakes

Confusing BSE with other neurological diseases is a common error. The clinical signs of BSE overlap with many conditions, and only laboratory testing can confirm the diagnosis. Assuming that atypical BSE is the same as classical BSE is another mistake. The forms differ in origin, tissue distribution, and zoonotic potential. Finally, assuming that prions can be inactivated by standard sterilization is incorrect. Prions require specialized decontamination protocols [4].

Individual cases require veterinary assessment. This article provides general information and does not replace professional diagnosis or treatment.

Frequently Asked Questions

What causes mad cow disease?

Mad cow disease is caused by a misfolded form of the prion protein called PrPSc. This abnormal protein converts normal PrPC into more copies of itself, leading to brain damage.

What are the symptoms of mad cow disease in cows?

Symptoms include nervousness, aggression, incoordination, difficulty standing, hyperesthesia, weight loss, and decreased milk yield. Signs typically appear in cattle 4 to 6 years old.

Can humans get mad cow disease?

Humans can develop variant Creutzfeldt-Jakob disease (vCJD) from consuming BSE-contaminated beef products. This is a rare but fatal condition.

How does mad cow disease spread?

The primary route is through contaminated feed containing meat-and-bone meal from infected cattle. Maternal transmission is a minor route. Direct cattle-to-cattle transmission is not significant.

Is mad cow disease the same as scrapie?

No. Scrapie affects sheep and goats, while BSE affects cattle. Both are prion diseases, but they are caused by different prion strains and have different transmission patterns.

How is mad cow disease diagnosed?

Definitive diagnosis requires postmortem examination of brain tissue, particularly the obex region. Tests include histopathology, immunohistochemistry, and Western blotting.

What is the feed ban?

The feed ban prohibits feeding ruminant-derived protein to ruminant animals. This measure breaks the feedborne cycle that drove the classical BSE epidemic.

Is there a treatment for mad cow disease?

No. BSE is always fatal. Affected cattle are typically euthanized on humane grounds. Control measures focus on prevention through feed bans, SRM removal, and surveillance.