Alzheimer’s disease may be a systemic disease, not just a brain disease

New research using fruit flies shows that not only does Alzheimer’s disease affect the brain, but also the disease proteins cause different patterns of damage throughout the body. Scientists have created the first complete single-cell map showing how two key Alzheimer’s proteins (Aβ42 and Tau) affect different tissues in dramatically different ways, providing new insights into patients’ development of this different symptoms.

The study, published in the journal Neuron, examined more than 600,000 single cells in 219 different cell types designed in Drosophila to develop the condition of Alzheimer’s. This comprehensive atlas of disease impacts could help scientists identify new biomarkers for early diagnosis and develop treatments for specific body systems affected by Alzheimer’s patients.

This study is particularly important because its whole-body approach is often seen as brain-centric. Can this broader view lead to how we understand and treat Alzheimer’s disease?

Different proteins, different body systems

The researchers found that there are significant differences in how each Alzheimer’s protein affects the body. When they express Aβ42 in Drosophila neurons (forming amyloid plaques in the human brain), the damage remains largely limited to the nervous system, with sensory neurons particularly fragile.

“The expression of Aβ42 mainly affects the nervous system. Sensory neurons involved in vision, audition and olfactory are particularly vulnerable. The decline in odor may be an early symptom of Alzheimer’s disease, and in this study we identified specific olfactory neurons affected by Aβ42 in fruit fruit.

These findings are consistent with what many people with Alzheimer’s have experienced, as they usually smell one of the earliest symptoms of the disease. Importantly, this study accurately points out which odor detection neurons are most affected.

Tau accelerates the aging of the whole body

Instead, when the researchers expressed tau protein in fly neurons (a neurofibrillary tangle forming in human Alzheimer’s disease), they observed widespread changes in the body’s peripheral tissues, especially the metabolism, digestive and reproductive systems.

“Tau expression in neurons leads to major changes, mainly in surrounding tissues, such as altering fat metabolism and digestion and reducing fertility. These changes mimic age-related changes, suggesting that Tau expression accelerates aging,” Co-First author Tzu-Chiao Lu lu lu lu lu lab of Lab lab in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib in li lib “We found that neuronal connectivity and other factors mediating brain body communication were disrupted in tau flies.”

These TAU-induced changes outside the brain are very similar to the commonly similar patterns in aging, suggesting that Tau protein may actually accelerate the aging process throughout the body.

Common characteristics across species

To determine if their findings were related to human disease, the researchers compared their fruit fly data with data sets of Alzheimer’s in mice and humans. They found an amazing pattern: a conserved cluster of “LDH high” cells (neurons with high lactate dehydrogenase content) are present in samples of Alzheimer’s in all three species.

This conservative signature suggests that similar cellular stress responses in human Alzheimer’s patients occur with Drosophila models, strengthening the flies’ findings that may translate into human disease.

The study also identified fat metabolism abnormalities in the Fly of tauopathy (Tau protein accumulation) and mouse models. These consistent patterns among these animals suggest that these changes may also occur in humans with Alzheimer’s.

A comprehensive body diagram of the effects of Alzheimer’s disease

This study represents the first comprehensive cellular atlas of Alzheimer’s disease in the entire organism, known as the “Alzheimer’s disease fly Atlas”. The team used single-nuclear RNA sequencing to speculate gene expression in a single cell of flies expressing Aβ42 or tau protein.

These findings describe pictures of Alzheimer’s as a systemic disease, with brain pathology triggering the cascade of the entire body:

• Sensory systems (vision, hearing, odor) are particularly susceptible to Aβ42 toxicity
• Activate endoplasmic reticulum stress response in neurons exposed to Aβ42
• Disregulation of fat metabolism in flies and tau-expressing mice
• Intestinal tissue shows signs of premature aging when exposed to tau
• Brain-body communication pathways are destroyed, especially tau

Impact on human diseases

This holistic view of Alzheimer’s disease can significantly influence how we understand, diagnose and treat the condition. By revealing how different tissues respond to Alzheimer’s proteins, researchers may be able to identify new biomarkers in blood or other easily accessible tissues.

“These and other findings described in Alzheimer’s disease, the fly-fly atlas, improves our understanding of how Alzheimer’s disease-related proteins Aβ42 and Tau affect the entire organism.” Bellen is an outstanding professor of molecular and human genetics services at Baylor and chair of neurogenetics at Duncan NRI.

The meaning of this study goes beyond fruit flies. If humans with Alzheimer’s have similar systemic effects in humans, doctors may need to monitor and address multiple body systems affected by the disease, not just the brain.

The research team has publicly obtained comprehensive Atlas to facilitate further investigations into neurodegenerative midbrain somatic connections. This resource provides the basis for exploring how Alzheimer’s disease affects the entire body and may accelerate the discovery of new treatments targeting the effects of these systems.