Neurodegenerative disease is an overarching term for a heterogeneous group of
chronic disorders, characterized by the progressive and
irreversible deterioration and death of nerve cells in the brain or the peripheral nervous system, gradually compromising mental functioning (dementia), ability to move (ataxia), speech (aphasia), and even breathing. While the exact etiology of the different neurodegenerative disorders is yet fully understood, the
individual's age is certainly one of the significant risk factors. Therefore, if the increasing life expectancy observed in the last decades is good news per se, it also implies that a growing number of individuals might be affected by these age-related pathologies. According to the 2019 World Health Organization guidelines (1), dementia affects 50 million people worldwide, and nearly 10 million new cases are registered every year. With the current progression, the total number is set to triple by 2050.
The devastating impact on the life of affected individuals, caregivers and families, and the financial burden they represent for each country render neurodegenerative diseases a growing public health concern. Unfortunately, no effective treatments exist to date, and in most cases, only symptomatic therapies are available. In fact, despite the progress in basic and preclinical research, we still lack information about the biology of these pathologies and the critical molecular defects that could represent effective drug targets. As always, the hope rests upon scientific research.
Alzheimer's disease
Alzheimer's disease (AD) is the most common neurodegenerative disorder and contributes to >60% of dementia cases worldwide. The loss of cognitive functions in AD patients includes progressive memory loss, mood and behavior alterations, disorientation, and aphasia. The gradual decline of physical abilities eventually leads to the total loss of autonomy (e.g., incapacity of communicating, walking, and swallowing). AD itself is not lethal, but death is usually caused by external factors facilitated by the condition, such as infections (i.e., pneumonia).
From a pathophysiological point of view, AD is characterized by the presence of specific protein aggregates in the brains of patients, known as amyloid plaques and neurofibrillary tangles. The
amyloid plaques are composed of aggregates of the
amyloid-β (Aβ) peptide, forming insoluble β-sheet fibrils within the brain's
extracellular space. The amyloid-β peptide is generated by the cleavage of a transmembrane larger glycoprotein, the
amyloid precursor protein (APP). Two proteases break down APP in two soluble fragments (sAPPα and sAPPβ) and a cell-membrane-bound fragment (C99). The latter is cleaved by an enzymatic complex (
γ-secretase) that releases the Aβ peptide and an intracellular peptide. The Aβ peptides can be made up of 40 (Aβ
1–40) or 42 (Aβ
1–42) amino acids.
Aβ1–42 is the less abundant form. Because of its composition, it has a propensity to aggregate forming oligomers, proto-fibrils, fibrils, and ultimately, the amyloid plaques characterizing AD (2). Contrary to amyloid plaques,
neurofibrillary tangles (NFTs) accumulate intracellularly within neurons. These are composed of a highly-phosphorylated form of the
microtubule-associated protein tau, causing cytoskeletal changes that disrupt axonal transport (2).
Looking for AD treatments: targeting beta-amyloid aggregates.
While it is yet not fully clear how beta-amyloid aggregates cause toxic damage, they certainly are one of the hallmarks of AD pathology. Therefore, according to the " '
amyloid cascade hypothesis ", they have been considered the central event of AD pathology, according to the " 'amyloid cascade hypothesis." Therapies aiming at the clearance of Aβ aggregates have been pursued. These are mainly based on three mechanisms: 1) increasing the elimination of Aβ; 2) inhibiting the accumulation of Aβ; and 3) regulating the production of Aβ (3).
An excellent overview of the strategies adopted so far can be found in recent review articles (2-4).
Active immunization, which relies on vaccines to elicit an immunological response against Aβ, has generated mixed results. One of the most promising candidates, CAD106 (which combines multiple copies of Aβ1–6 peptide coupled to a virus-like particle), has been recently terminated (5), and no vaccine is yet to pass the clinical trial phase.
Passive immunotherapy, which relies on humanized anti-Aβ antibodies, has been one of the most haunted paths. The FDA has recently approved
Aducanumab (marketed as Aduhelm; Biogen Inc) to treat Alzheimer's disease. Aducanumab is a recombinant human IgG1 antibody that binds to soluble Aβ aggregates and insoluble fibrils with a >10,000-fold selectivity over monomers (6). Unfortunately, its use remains quite controversial. In 2019, the late-stage clinical trial was stopped because no beneficial effects on memory loss and cognitive impairment were found. However, later that same year, the results from another trial led Biogen to conclude that the drug could work if administered in higher doses. While the advisory committee voted against the new data, the FDA decided to approve Aducanumab under the "accelerated approval" pathway, based on its ability to lower the levels of amyloid plaques in the brain. The FDA deemed the treatment "likely," yet not sure, to help patients (7). The definitive approval is on the condition that the treatment demonstrates actual clinical benefits.
The third option to try and reduce the Aβ accumulation is to regulate its production. For this reason, BACE1 is considered a relevant target as it is one of the enzymes involved in APP processing. A few BACE1 inhibitors entered the clinical trial phase but are yet to be approved.
What are the current methods and challenges of testing for neurodegenerative diseases?
The current methods of diagnosis for these diseases often are not sensitive enough for early detection, and thus by the time of diagnosis, significant neurodegeneration has occurred for decades. Except for genetic testing (for example, autosomal dominant mutations in the APOE gene), clinicians have had to rely on patient reports of cognitive decline, which is unreliable and inconsistent, as well as invasive and expensive testing methods to properly diagnose a patient. For example, Aβ imaging via PET scan by which radioactive tracers such as Florbetapir (18F) are injected into the patient and bind to Aβ in the person's brain to be seen on imaging. However, these PET Scans are not always definitive because neurodegenerative diseases can look similar via PET scan, thus, making targeted treatment challenging to create the best outcome for the patient based on their specific disease. Tau or amyloid testing of the patient's cerebrospinal fluid (CSF) is also a method for diagnosis. However, it is quite invasive given the nature of extracting CSF safely. Furthermore, these biomarkers are still present for a variety of neurodegenerative diseases, resulting in inconclusive diagnoses. Taken together, the need for next-generation biomarkers to detect the onset of neurodegenerative diseases and distinguish between pathologies is a fundamental next step in science and healthcare.
Looking for AD treatments: new strategies
Over the last decades, except for the debated Aducanumab, all the treatments targeting the Aβ accumulation failed to demonstrate any beneficial outcome for AD patients, even when reducing amyloid peptides deposits. One reason for these failures is that Aβ accumulation might be less strongly connected to AD neurodegeneration than originally envisaged with the amyloid cascade hypothesis. For example, there is only a weak correlation between Aβ plaques and the severity of clinical symptoms. Some individuals might be positive for some neurodegeneration biomarkers with no Aβ deposits. Indeed, in some autopsy studies, tau pathology has been observed before marked Aβ deposition, and not the other way round (2).
There is, therefore, an increased focus on the development of alternative strategies to treat AD patients. Since
tau pathology correlated better with cognitive impairments, immunotherapies targeting tau are under clinical trials. An alternative option, also encouraged by the World Health Organization, is the intervention on the modifiable risk factors for developing AD.
Type 2 diabetes is the first target on the list. Insulin has a fundamental neurotrophic effect on the brain, and insulin resistance seems to render neurons more vulnerable to stress and damage. Anti-diabetes treatment could, therefore, represent a new approach to treat AD. Preliminary results supporting this hypothesis show promise (7): in a pilot clinical trial, a four-month intranasal insulin administration was shown to improve memory in AD patients.
Finally, neuro-inflammation is well-known to be linked with neurodegenerative diseases. Microglia cells were found to co-localize with amyloid plaques in the brains of AD patients, indicating a potential interaction between these cells and one of the essential pathological hallmarks of AD (8). Therefore, a deeper understanding of the biology of innate immune response cells might give key indications towards the development of new drugs.
An Enzo Viewpoint
From this brief overview, it clearly appears that the molecular mechanisms underlying neurodegenerative disorders' causes, onset, and evolution, need to be further investigated to develop new and hopefully more effective therapeutic strategies. Enzo supports your research on neurodegeneration with a rich portfolio of products, ranging from relevant biomarkers to tools to investigate altered cellular processes (Figure 1) finely.
