CELLULAR AND VASCULAR MECHANISMS IN NEURODEGENERATION

S. Lomoio^*

Alzheimer’s Disease Research Laboratory, Department of Neuroscience, Tufts University School of Medicine, Boston, United States.

*Correspondence to:
Selene Lomoio,
Alzheimer’s Disease Research Laboratory,
Department of Neuroscience,
Tufts University School of Medicine.
e-mail: Selene.lomoio@tufts.edu

Received: 01 September, 2025 Accepted: 11 December, 2025

ISSN 2279-5855 print ISSN 2974-6345 online. Copyright © by BIOLIFE 2025 This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

ABSTRACT

Neurodegeneration is a brain disorder characterized by the death of neurons. It occurs in many brain diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). The causes of neurodegeneration are poorly understood and still under study. However, it is known that excessive production of reactive oxygen species (ROS) can damage DNA, as well as some proteins, lipids, and other cellular structures. Mitochondria regulate programmed cell death, or apoptosis, but when they are damaged in neurodegeneration, they reduce ATP levels and increase ROS levels. This affects neurons, which are particularly vulnerable to mitochondrial dysfunction. In neurodegenerative diseases, damaged mitochondria accumulate, leading to apoptosis.

KEYWORDS: Neurodegeneration, mechanisms, neurodegenerative diseases, amyloid beta, a-synuclein, reactive oxygen species

INTRODUCTION

Neurodegeneration is characterized by the loss of neurons that can occur in many brain diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), when abnormal proteins accumulate (1,2). For example, in AD, amyloid beta (Aβ) accumulates; while in PD, a-synuclein aggregates, or Lewy bodies, form (1-3). Abnormal protein aggregates are toxic to neurons and interfere with their function. The causes of these protein abnormalities are diverse and often unclear.

It is known that excessive production of reactive oxygen species (ROS) can damage DNA, proteins, lipids, and other vital cell structures (4). Neurons are particularly affected by ROS because they consume large amounts of oxygen and have little antioxidant capacity. Energy-producing mitochondria can undergo mutations and contribute to neurodegeneration.

DNA damage and repair defects can be harmful to the life of the neuron (5). Mitochondrial damage reduces ATP and increases ROS levels, altering the mitochondrial membrane potential, releasing cytochrome C, and activating apoptosis (6). Mitochondria produce ATP through oxidative phosphorylation and control intracellular calcium levels (7). They also regulate programmed cell death or apoptosis, and the balance between oxidation and reduction reactions within a cell (8). Being high-energy, post-mitotic cells, neurons are particularly vulnerable to mitochondrial dysfunction. Decreased ATP production compromises synaptic function and neuronal signaling (9) (Fig.1).

Fig. 1. Neurodegeneration is characterized by neuronal damage, protein aggregation, mitochondrial dysfunction, and oxidative stress that cause apoptosis and the loss of neurons.

Neurodegeneration is characterized by apoptosis, ferroptosis, pyroptosis, and necroptosis (10). These changes begin at the synaptic level, before neuronal death occurs. Neurodegeneration leads to impaired neurotransmitter formation, with the onset of numerous neurological and psychiatric disorders, depending on the type of neurotransmitter involved (1) (Table I).

Table I. The characteristics of neurodegeneration.

DISCUSSION

CNS diseases can be neurodegenerative, vascular, inflammatory, and neoplastic, affecting cerebral blood vessels, the BBB, neurons, and glial cells. Neurodegeneration involves the progressive loss of neuronal structure and function due to protein misfolding, inflammation, and oxidative stress. Neurodegeneration is closely linked to the vascular system, resulting in reduced blood flow, small infarcts, and BBB damage. Pathological proteins such as Aβ deposit in the vessels, causing cerebral angiopathy with inflammation that alters the endothelium and vascular dementia. Risk factors include hypertension, hypercholesterolemia, and diabetes.

In PD, when cellular autophagy fails, damaged mitochondria accumulate, leading to apoptosis through the release of cytochrome C (11). Oxidative stress also leads to the accumulation of α-synuclein (12). In AD, mitochondria interact with the Aβ protein, altering oxidative phosphorylation (11). Early mitochondrial damage often occurs in the preclinical stages. In amyotrophic lateral sclerosis (ALS), mutations in SOD1, TDP-43, and FUS result in increased oxidative stress and mitochondrial dysfunction (13). Therapeutic implications for neurodegenerative disorders include mitochondrial antioxidants, such as CoQ10, modulators of mitochondrial dynamics, and gene therapies to correct PINK1/Parkin mutations (14).

Excessive glutamate release causes hyperactivation of NMDA/AMPA receptors, leading to the influx of calcium ions and cell damage (15). The activation of lytic enzymes such as calpains and caspases is also harmful to neurons (16). Calpain activation in neurons is a very important process, both physiologically and pathologically (17). Calpain is a family of proteases, enzymes that degrade proteins and are activated by calcium. The main isoforms in the brain are calpain-1, which is activated by low Ca2⁺ concentrations (18); and calpain-2, which is activated by higher Ca2⁺ concentrations. When cerebral ischemia or any trauma occurs, calpain is hyperactivated, causing the degradation of structural proteins, breakdown of the blood-brain barrier (BBB), mitochondrial damage, and disruption of synaptic signaling (19).

Caspases are a family of proteolytic enzymes (20) that can be activated in neurons, where they play a key role in apoptosis, a process essential for eliminating excess neurons and refining synaptic connections. Caspase-3 is often implicated in pathological conditions such as ischemia, oxidative stress, stroke, and traumatic brain injury (21). The phenomenon of altered neuronal survival involves the reduction of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), the increase of pro-apoptotic signals such as Bcl-2-associated X protein (BAX), and the reduction of anti-apoptotic signals such as Bcl-2 (22).

BDNF is a neurotrophic factor essential for the survival, development, synaptic plasticity, and function of neurons. It belongs to the neurotrophin family, which also includes nerve growth factor (NGF), NT-3, and NT-4/5 (23). BDNF promotes the survival of neurons during development and prevents apoptosis, increases the effectiveness of existing synapses, and stimulates the formation of new synapses and new neurons, especially in the hippocampus (24).

BAX is a pro-apoptotic protein belonging to the Bcl-2 family and plays a crucial role in regulating apoptosis (25). Under conditions of hypoxia, oxidative stress, and other cellular insults, BAX is activated and translocates from the cytosol to the mitochondrion, where it promotes the release of cytochrome C (26). This activates the mitochondrial apoptosis pathway, leading to the activation of caspases that degrade the cell and cause neuronal death. Bcl-2 regulates apoptosis and plays a fundamental role in neuronal survival both during nervous system development and in pathological conditions. In neurons, Bcl-2 inhibits apoptosis by blocking the release of cytochrome C from mitochondria, thus preventing the activation of the caspase cascade (27).

Chronic inflammation, with the activation of microglia, caspases, and pro-inflammatory cytokines such as TNF and IL-1β, are detrimental to neuronal survival (28).

There is no specific therapy for neurodegeneration; however, drugs and other methods are used to slow the progression of the disease, manage symptoms, and improve quality of life. Some medications may be helpful, such as those that inhibit cholinesterase, the N-methyl-D-aspartate (NMDA) antagonist, and monoclonal antibodies against Aβ in AD (29).

Cholinesterase inhibitors

Cholinesterase inhibitors (anticholinesterases) are responsible for the degradation of acetylcholine (ACh) in the sympathetic nervous system and act on the enzyme acetylcholinesterase, reducing its effect (30). Acetylcholinesterase breaks down ACh into choline and acetate. The inhibitors bind to the enzyme’s active site, preventing hydrolysis, increasing the amount and duration of action of ACh at cholinergic synapses, and improving neurodegeneration (31). Increased ACh in synapses causes prolonged stimulation of muscarinic and nicotinic cholinergic receptors (32). At the cellular level in the CNS, there is an increase in cholinergic transmission and an improvement in sympathetic function, memory, and learning. At the peripheral nervous system level, there is both sympathetic and parasympathetic stimulation in the autonomic ganglia, while at the neuromuscular junction, there is prolonged depolarization (33).

N-methyl-D-aspartate (NMDA) antagonist

NMDA receptor antagonist drugs inhibit the activity of ionotropic glutamate receptors, playing a fundamental role in excitatory synaptic transmission, neuronal plasticity, and learning and memory processes (34). The NMDA receptor is an ion channel activated by glutamate, but activation requires a co-agonist such as glycine or D-serine, as well as the removal of the blockade by Mg²⁺ ions. These antagonists can act at different levels and can be classified as competitive, noncompetitive, glycine-site antagonists, and allosteric negative modulators (35). Competitive antagonists bind to the glutamate binding site, preventing its activation; noncompetitive antagonists bind to an allosteric site or within the channel and block ion flow even if glutamate is bound; glycine-site agonists inhibit the binding of glycine to its co-agonist site on the NMDA receptor; while allosteric negative modulators act by altering the receptor’s conformation, reducing its activity (36).

Monoclonal antibodies against amyloid-beta (Aβ)

Monoclonal antibodies against Aβ are one of the most widely studied therapeutic strategies for the treatment of AD (37). Monoclonal antibodies are designed to specifically recognize and bind to the Aβ protein, responsible for the formation of senile plaques that characterize AD. These antibodies bind to different forms of Aβ that consist of soluble monomers (Aβ1-40, Aβ1-42), toxic oligomers, and insoluble fibrils. Monoclonal antibodies neutralize the toxic soluble forms of Aβ, particularly the oligomers, which are thought to be the most damaging to synaptic function (38). After binding to the plaque, the antibody promotes its removal through phagocytosis by microglia and complement activation. Microglia recognize antibodies bound to Aβ via Fcγ receptors, inducing phagocytosis of the plaques (39). However, during phagocytosis, immune cells produce pro-inflammatory cytokines (IL-1 and TNF) that contribute to neuronal neurodegeneration.

CONCLUSIONS

Neurodegeneration is characterized by neuronal loss and damage to DNA, proteins, and lipids. In AD, it is caused by the accumulation of the protein beta-amyloid (Aβ), and in PD, it results in the formation of aggregates of α-synuclein. These diseases result in mitochondrial damage and impaired ATP production, leading to neuronal damage. Impaired neuronal survival results in a reduction of BDNF, an increase in pro-apoptotic signals such as BAX, and a reduction in anti-apoptotic signals such as Bcl-2. The onset of conic inflammation leads to the activation of microglia, caspases, and pro-inflammatory cytokines. To date, specific therapy for neurodegeneration is lacking. Monoclonal antibody therapy has been shown to neutralize various forms of Aβ in AD; however, therapies related to neurodegeneration often produce inflammation and are ineffective. Further studies are needed to develop satisfactory therapies.

Conflict of interest

The author declares that they have no conflict of interest.

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