Alzheimer’s disease (AD) is the most common type of dementia and is currently incurable. It effects approximately 5.5 million Americans and is the sixth leading cause of death in elderly individuals. The disease is caused by a plaque formation of amyloid beta (Aβ) in the brain. Currently, there is no cure for Alzheimer’s disease however there are five FDA approved drugs to slow the progression of Alzheimer’s disease.
Research into this disease has conventionally focused on the CNS, however, several peripheral and systemic abnormalities are now understood to be linked to AD. This has led to pursuit of understanding how altercations can contribute to AD and the creation of therapies and treatments to prevent them from occurring. As, dementia carries significant implications for patients, their families, and our society, it is imperative to determine the cause and pathway of this disease. More research focused on finding and understanding what triggers the initiation of Aβ plaque production in the brain can lead to the discovery of a treatment for this condition.
An imbalance between the production and clearance of Aβ is an early, an often initiating, factor in Alzheimer’s disease. Previous studies focused on targeting amyloid-β formation as a hopeful treatment of Alzheimer’s disease. One study attempted to regulate amyloid beta formation via immunotherapy. Amyloid-β targeting antibodies were used to prevent the formation of amyloid beta plaques, a hallmark condition of Alzheimer’s disease.
Mouse models were used to study two different antibodies against amyloid beta formation. Results indicated a decrease in Aβ production, an increase in hyperactivity in the cortical area, and persisting neuronal dysfunction. The increase in hyperactivity indicated neuronal synchrony, a positive indication, and so, research was redirected to finding a treatment for the neuronal dysfunction. An experiment with monoclonal antibody, 3D6 and mice resulted in a decrease of Aβ formation in the brain, also a positive indication.
Research focus was then shifted again to determine whether if neuronal dysfunction could be treated prior to plaque formation, in the earlier stages of Alzheimer’s disease. Increased hyperactivity was observed upon administration of 3D6 antibody to the mice, this indicated that antibody 3D6 exhibited a pro-excitatory effect that is dependent on the over expression of APP. Results also showed that mice treated for 5 months with β1 exhibited reduced amounts of amyloid β plaque production however this amount of reduction was less than what was observed compared to treatment with 3D6. Treatment with 3D6 provided a consistent affect of reduced aggravation. A 3-month study with β1 antibodies to see if they also provided a consistent affect was performed.1 Results implied an increase in hyperactivity in the cortical area, but overall had no large impact on treatment performance.
A conclusion was drawn that the reduction in amyloid beta plaque formation contributes to the aggravation of neuronal impairments. An additional study based on the role inflammation on the amyloid-β antibodies responsible for hyperactivity was performed. Results demonstrated that inflammatory reactions did not affect levels of, nor had a role in the level of hyperactivity observed in the cortical region of the brain. The compilation of the studies concluded that the treatment of amyloid beta plaques with antibodies to Aβ did not treat neural dysfunction but in fact worsened it. Further research, investigate to the repair of neuronal dysfunction needs to be performed.1
BRCA1 has been determined to be central to learning and retaining memories. Gladstone researchers theorized that the cycle of DNA damage and repair in the brain is what facilitates the learning process.5 Decreased levels of this protein is exhibited in patients with Alzheimer’s disease and leads to degeneration of cognitive function, which is a hallmark symptom of the pathology. Amyloid beta plaque formation can be associated with proteins such as BRCA1 and presenilin 1 expression, which would explain why neural dysfunction is present despite the inhibition of amyloid beta plaques and an increase in hyperactivity in cortical regions of the brain. This also reaffirms previous studies suggesting that impairment of neurons involved in cognitive processing can be present despite significant increases in hyperactivity and hyperexcitation in the cortical regions. This research provides insight as to how to stop the formation of amyloid beta plaques and also creates a foundation into why neuronal dysfunction is still present.
Intracellular tau protein tangles have also been indicated as a biomarker in the molecular pathogenesis and studies have indicated that AD is most likely an amyloid-enabled tauopathy and amyloid plaque production defines the stage of the disease.4 This is a significant finding because Tau’s function is in the assembly and stabilization of microtubule structure. Studies based on the role of tau in neurodegeneration presents a therapeutic target for the pathology in addition to the measurement of amyloid- β plaques.
Other studies have focused on alterations of local neuronal circuits, due to amyloid plaques, and the role they play in Alzheimer’s disease. Soluble Aβ oligomers and amyloid plaques alter neuronal circuits and other networks by disrupting the balance of synaptic excitation and inhibition (E/I balance) in the brain. It was discovered that hyperactivity in cortical regions precede the formation of amyloid Aβ plaque formation and could be the reason neuronal dysfunction persists despite inhibition of Aβ plaque formation. Therapies that can correct the E/I balance during the extended early phase of AD may prevent neuronal dysfunction, cell loss and cognitive impairments associated with later stages of AD.1
Moving forward we can expect a shift in focus, prioritizing intervention at the synaptic level prior to neuron degeneration is promising in the study of Alzheimer’s disease and prevention. Identifying signals of declining synaptic health is vital to establishing measurable biomarkers to help identify the onset of AD. Biomarkers currently being researched are amyloid beta and tau proteins, however a note of importance is placed on identifying reliable early detection methods because early diagnosis gives the patient access to treatments to slow the progression of neuronal degeneration. This can provide retention of cognitive abilities, a better quality of life and a longer survival period after diagnosis.
