3.10.1 Neuropathology of neurodegeneration and surrounding controversies

Neuropathology of Neurodegeneration

Neurodegeneration refers to the gradual loss of structure or function of neurons, resulting in cognitive or motor deficits. It is a common feature of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic lateral sclerosis (ALS). Understanding the neuropathology of neurodegeneration is essential to understanding the underlying mechanisms of these diseases and developing effective treatments.

At the cellular level, neurodegeneration is characterized by the presence of neurofibrillary tangles, Lewy bodies, and inclusions. Neurofibrillary tangles are aggregates of hyperphosphorylated tau protein, which is normally present in the cytoplasm of neurons. In Alzheimer’s disease, neurofibrillary tangles are found in the hippocampus and cortex, where they are thought to disrupt neuronal function and contribute to cognitive decline. Lewy bodies are protein inclusions found in the neurons of Parkinson’s disease patients and are composed of aggregated alpha-synuclein. The formation of Lewy bodies is thought to be a result of oxidative stress and inflammation, leading to cell death and the progressive degeneration of dopamine-producing neurons in the substantia nigra.

Another hallmark of neurodegeneration is the presence of amyloid plaques, which are extracellular deposits of beta-amyloid protein. In Alzheimer’s disease, amyloid plaques are thought to be a result of the accumulation of beta-amyloid peptides, which are cleaved from the amyloid precursor protein. The accumulation of amyloid plaques is thought to be toxic to neurons and contributes to cognitive decline.

Inflammation also plays a role in neurodegeneration. Chronic low-grade inflammation has been observed in several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and ALS. The precise mechanisms by which inflammation contributes to neurodegeneration are not well understood, but it is thought to be related to oxidative stress, excitotoxicity, and the activation of microglia, which are resident immune cells in the central nervous system.

In addition to these cellular changes, neurodegeneration is also associated with changes in neurotransmitter systems. In Parkinson’s disease, for example, the loss of dopamine-producing neurons leads to decreased dopamine levels, leading to motor symptoms such as tremors and rigidity. Similarly, in ALS, the loss of motor neurons results in the degeneration of motor pathways and the development of muscle weakness and atrophy (Love, 2005).

In summary, the neuropathology of neurodegeneration is complex and multi-faceted and is characterized by cellular changes such as the presence of neurofibrillary tangles, Lewy bodies, and amyloid plaques, as well as inflammation and changes in neurotransmitter systems. Understanding these changes is essential to understanding the underlying mechanisms of neurodegenerative diseases and developing effective treatments (McKeith, 2005)

Dementias can be classified in three ways:

Classification:	Example:
Aetiology	Alzheimer’s disease, vascular dementia, dementia with Lewy bodies and Frontotemporal dementia
Anatomy	Cortical, subcortical, mixed
Molecular pathology	Tauopathies, synucleinopathies and ubiquitinopathies

(Houlden, 2010),

Controversies in the Pathophysiology of Neurodegeneration

The pathophysiology of neurodegeneration is a complex and rapidly evolving field, and there are several ongoing controversies regarding the underlying mechanisms of neurodegenerative diseases. Some of the most notable controversies include the role of protein aggregation, oxidative stress, neuroinflammation, and neurovascular dysfunction. In this discussion, we will examine each of these controversies in more detail.

Protein Aggregation: One of the most well-established hallmarks of neurodegeneration is the accumulation of protein aggregates, such as neurofibrillary tangles and amyloid plaques. However, there is an ongoing debate about the precise role of protein aggregation in neurodegeneration. While some researchers argue that protein aggregates are the direct cause of neurodegeneration, others argue that they are simply markers of disease and that other factors, such as oxidative stress, neuroinflammation, and neurovascular dysfunction, play a more significant role.

Oxidative Stress: Oxidative stress, which is the result of an imbalance between the production of reactive oxygen species and the ability of cells to neutralize them, has been implicated in several neurodegenerative diseases. However, there is an ongoing debate about the precise role of oxidative stress in neurodegeneration. While some researchers argue that oxidative stress is a direct cause of neurodegeneration, others argue that it is simply a secondary phenomenon that results from other factors, such as protein aggregation, neuroinflammation, and neurovascular dysfunction (Pan, 2017).

Neuroinflammation: Chronic low-grade neuroinflammation has been observed in several neurodegenerative diseases, and has been implicated as a possible cause of neurodegeneration. However, there is an ongoing debate about the precise role of neuroinflammation in neurodegeneration. While some researchers argue that neuroinflammation is a direct cause of neurodegeneration, others argue that it is simply a response to other factors, such as protein aggregation, oxidative stress, and neurovascular dysfunction.

Neurovascular Dysfunction: Recent research has suggested that neurovascular dysfunction, which is characterized by alterations in the blood-brain barrier and cerebral blood flow, may play a role in neurodegeneration. However, there is an ongoing debate about the precise role of neurovascular dysfunction in neurodegeneration. While some researchers argue that neurovascular dysfunction is a direct cause of neurodegeneration, others argue that it is simply a consequence of other factors, such as protein aggregation, oxidative stress, and neuroinflammation (McGeer, 2002).

The pathophysiology of neurodegeneration is a complex and rapidly evolving field, and there are several ongoing controversies regarding the underlying mechanisms of neurodegenerative diseases. While the precise role of protein aggregation, oxidative stress, neuroinflammation, and neurovascular dysfunction in neurodegeneration remains uncertain, it is clear that these factors are interrelated and that a more comprehensive understanding of the pathophysiology of neurodegeneration will require a more integrated and multidisciplinary approach (Zlokovic, 2011).

References:

(1) Houlden, H., Baker, M., Morris, H. R., & Whittaker, J. (2010). Tauopathies. Brain, 133(2), 312-326.

(2) Love, S. (2005). Neuropathological investigation of dementia: a guide for neurologists. Journal of Neurology, Neurosurgery & Psychiatry, 76(suppl 5), pp.v8–v14.

(3) McGeer, P. L., McGeer, E. G., & Suzuki, J. (2002). The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain research. Brain research reviews, 39(1), 1-64.

(4) McKeith, I. G., Dickson, D. W., Lowe, J., Emre, M., O’Brien, J. T., Feldman, H., & Cummings, J. (2005). Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology, 65(12), 1863-1872.

(5) Pan, Y., & Kasturi, P. (2017). The role of oxidative stress in neurodegenerative diseases. Journal of neural transmission, 124(4), 391-406.

(6) Zlokovic, B. V. (2011). Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nature reviews Neuroscience