Neurodegeneration refers to the slow, progressive loss of structure and function of neurons, the highly specialized cells that underpin our nervous system1. Unlike most other cell types in the body, neurons are, for the most part, irreplaceable. If lost, the effects are mostly irreversible, leading to a gradual but inexorable decline in brain and nervous system function. This process is behind some of the most devastating conditions in medicine, as it destroys memory, movement, personality, and autonomy. With the world’s population aging at an alarming rate, neurodegenerative illnesses are emerging as a world health crisis, imposing tremendous burdens on families, healthcare systems, and societies. The majority of such diseases are still incurable, with treatments available only to provide temporary relief or management of symptoms.
The faces of neurodegeneration
Alzheimer’s disease (AD)
Alzheimer’s disease is the most frequent culprit behind dementia, progressively stealing away memory, logic, and the skill to carry out activities of daily living2. Its hallmarks are the accumulation of amyloid-beta plaques between the neurons and coiled tangles of tau protein within them3. Such protein accumulations interfere with communication and eventually kill brain cells, causing the characteristic cognitive deterioration.
Parkinson’s disease (PD)
Parkinson’s disease is primarily recognized as a movement disorder, with tremor, muscle rigidity, and slowing of movement being key features4. The cause of the condition is the degeneration of dopamine-secreting neurons in an area of the brain known as the substantia nigra. Inside these dying cells, abnormal aggregates of alpha-synuclein protein, or Lewy bodies, form, which further disrupt neuronal activity5.
Amyotrophic lateral sclerosis (ALS)
ALS, also referred to as Lou Gehrig’s disease, targets the motor neurons responsible for controlling the voluntary muscles6. As these neurons degenerate, patients suffer from worsening muscle weakness, paralysis, and finally, respiratory failure. The disease is swift and relentless, and although there are some known genetic mutations, its exact cause often eludes diagnosis.
Huntington’s disease (HD)
Huntington’s disease is an inherited disorder caused by an expanded repeat in the gene for huntingtin7. It takes the form of a combination of uncontrollable movements (chorea), mental deterioration, and psychiatric symptoms. The mutant huntingtin protein is harmful to brain cells, and progressive loss of both mental and motor ability ensues.
Other neurodegenerative diseases
In addition to these, a range of other disorders— frontotemporal dementia (FTD), multiple sclerosis (MS), and the prion diseases, serve to show the wide variety of ways in which the nervous system can unravel8-10. Each has its own set of clinical features, but all share the same tragic commonality: progressive loss of neurons.
The molecular and cellular mechanisms behind neurodegeneration
Protein misfolding and aggregation
A common theme in neurodegeneration is protein misfolding and aggregation11. In normal cells, proteins are carefully folded into precise conformations. When this process fails, misfolded proteins aggregate into poisonous clumps, amyloid plaques in AD, Lewy bodies in PD, TDP-43 inclusions in ALS, and huntingtin aggregates in HD12. These protein clumps disrupt the cell machinery and communication, and could trigger direct cell death. It is not yet proven whether or not these aggregates are the primary underlying cause of the disease13.
Mitochondrial dysfunction
Neurons are one of the most energy-demanding cells in the body, relying on mitochondria— the powerhouses of the cell, to drive their function14. When mitochondria fail, neurons experience energy deficits, heightened oxidative stress, and accumulation of toxic byproducts15. This mitochondrial dysfunction makes neurons particularly susceptible to damage and is a unifying factor in many neurodegenerative disorders.
Oxidative stress and free radical damage
The brain is highly sensitive to oxidative stress resulting from mitochondrial dysfunction, a condition in which the generation of reactive oxygen species (ROS) exceeds the antioxidant defense of the cell16. ROS can cause damage to DNA, proteins, and lipids and thereby slowly impair the structural integrity and function of neurons. This oxidative injury is both a cause and effect of other pathological processes in neurodegeneration.
Neuroinflammation: microglial and astrocyte dysfunction
The brain’s own immune cells, microglia and astrocytes, are double-edged swords17-19. They perform housekeeping, cleaning up debris and assisting neurons when they work properly. But being constantly activated can turn them into sources of inflammation, releasing chemicals that damage neurons further and accelerate disease progression20. This transition from protective to damaging roles is an active area of research.
Defective proteostasis: protein quality control breakdown
Cells depend on complex machinery to recognize and remove misfolded or damaged proteins. The quality control machinery has two principal systems, namely the ubiquitin-proteasome system and the autophagy-lysosomal pathway21, 22. When these systems get saturated or are compromised, toxic proteins accumulate, overwhelming neurons and accelerating their death.
Synaptic dysfunction
Well before neurons degenerate and die, their connections— synapses, start to collapse. This initial synaptic failure disrupts the networks necessary for communication used for memory, motor function, and thought23. It is now recognized as a primary and reversible component of numerous neurodegenerative conditions, presenting a potential target for treatment.
Axonal transport deficits
Neurons are extended, differentiated cells dependent on effective transport systems to shuttle nutrients, organelles, and signaling molecules along their axons. Impairment of this axonal transport can deprive remote regions of the neuron of essential nutrients, leading to dysfunction and eventually, cell death24.
Genetic factors
Although the majority of neurodegenerative diseases are sporadic, genetics are a major player. Mendelian mutations in genes such as APP, PSEN1/2 (in Alzheimer’s), SNCA, LRRK2, GBA (seen in Parkinson’s), and SOD1, C9orf72 (found in ALS) may lead to familial disease forms25-27. Furthermore, certain genetic risk factors, the APOE4 allele in Alzheimer’s being an example, predispose to susceptibility in the general population at large28.
Environmental factors
The environment also influences neurodegenerative risk. Exposure to toxins, infections, head trauma, and lifestyle factors such as diet, exercise, and sleep habits can all affect the onset and progression of disease29. The interaction between genes and environment is an important area of current investigation.
Frontiers in neurodegeneration research
Targeting protein aggregation
One of the most aggressively explored areas of drug development involves targeting the misfolded proteins that accumulate in the brain. Scientists are working on designing small molecules and antibodies to inhibit misfolding, facilitate clearance, or prevent aggregation30, 31. In Alzheimer’s and Parkinson’s, these strategies are at the forefront of clinical trials, though challenges still persist.
Gene therapies and antisense oligonucleotides
Gene therapies are opening new avenues32. Antisense oligonucleotides have already demonstrated efficacy against spinal muscular atrophy and are being evaluated for HD, ALS, and even AD33. Early gene editing studies using CRISPR aim to repair or inactivate disease-triggering mutations, though clinical translation still remains on the horizon34.
Immunotherapies
Harnessing the immune system to clear toxic proteins, an immunotherapy approach, also serves for a promising approach. Monoclonal antibodies against amyloid-beta or tau in AD, or alpha-synuclein in PD, are under development and evaluation, and some have already made it to patients35-37. One prominent example would be Aducanumab, sold as Aduhelm, that targets amyloid-beta plaques in AD38. This work, alongside efforts to understand the immune system’s complex role in brain health, falls under the rapidly growing field of neuroimmunology.
Modulating neuroinflammation
Considering the contribution of chronic inflammation, medications that act on unique inflammatory pathways or regulate microglial function are under investigation as neuroprotective therapies39. The hope is to restore the balance towards a supportive, instead of harmful, immune response in the brain.
Mitochondrial enhancers
Compounds that enhance mitochondrial function and limit oxidative stress are under investigation as a means of protecting neurons and decelerating disease advance40. Although still in experimental stages, these strategies represent the increasing awareness of energy metabolism in neurodegeneration.
Stem cell therapies
Stem cell research holds promises for regenerating lost neurons or providing support to those that survive41. Stem cell transplantation or implantation of neurons from induced pluripotent stem cells (iPSCs) is being investigated, particularly in people with Parkinson’s disease. Stem cells could also deliver neurotrophic factors that help maintain neural circuits42.
Biomarker discovery and advanced imaging
Early and precise diagnosis is vital to successful intervention. Scientists are looking for biomarkers in blood, cerebrospinal fluid, making use of advanced imaging methods such as Positron emission tomography (PET) and magnetic resonance imaging (MRI)43. All of these tools can identify pathological changes, for instance, amyloid plaques or tau tangles, before symptoms manifest, paving way for more prompt and specific treatments.
The gut-brain axis
An unexpected frontier is the impact of the gut microbiome on overall brain health44. Recent evidence indicates that gut bacteria are able to modulate inflammation, metabolism, and even protein misfolding in the brain. This unlocks new avenues for therapies aimed at the gut-brain axis.
AI and machine learning
Artificial intelligence (AI) is revolutionizing neurodegeneration research45. Through extensive scrutiny of enormous data sets from genomics, clinical data, and imaging, AI can detect disease patterns, predict their progression, and expedite drug development, bringing precision medicine closer to reality. These technological advancements in understanding and manipulating the nervous system are central to the field of neuroengineering.
Challenges in neurodegeneration research
Neurodegeneration research, despite remarkable progress, faces formidable challenges. The intricacy of these diseases, based on an ensemble of genetic, molecular, and environmental factors, defies straightforward solutions. The majority of diseases are detected late, when substantial neuronal loss has already taken place, thus complicating early intervention. The symptom and course heterogeneity, even within the same disease, makes diagnosis and treatment challenging.
The blood-brain barrier (BBB) continues to pose an insurmountable obstacle to drug delivery to the central nervous system. This problem has driven research into innovative drug delivery strategies, including the use of nanoparticles and implantable nanocarriers designed to cross or bypass the BBB and target relevant regions in the brain for regenerative processes46.
Conventional models based on animals do not accurately portray the entire range of human diseases, which has led to the creation of human brain organoids and patient-derived iPSC models47-49. Organoids recapitulate complex brain architecture and cell diversity, including neural stem cells and various neuron subtypes relevant to diseases like PD, ALS, and AD, providing a more physiologically relevant environment compared to traditional 2D cultures. iPSCs can differentiate into neural lineages, including neurons and glial cells, allowing researchers to study disease mechanisms in a patient-specific context.
Lastly, ethical issues, particularly involving gene editing and novel brain treatments, must be navigated judiciously50.
Toward a future of brain health
Despite the fact that neurodegenerative diseases are still among medicine’s most daunting challenges, the pace of discovery is gaining momentum. Advances in basic research, technology, and cross-disciplinary collaboration are bringing us towards effective diagnosis, disease-modifying interventions, and ultimately a cure. The focus is shifting to early diagnosis, prevention, and personalized medicine, with the hope that one day, perhaps, the brain’s decline could be arrested or even reversed51. In this battle for the mind, each saved neuron is a triumph, and each scientific advance brings us closer to a future where neurodegeneration is not a death sentence.