Biochemistry of Alzheimer's disease

Flow chart depicting the role of apomorphine in Alzheimer's disease.

Alzheimer's Disease (AD) is one of the most prevalent causes of dementia in adults, yet its biochemistry remains incompletely understood. Recognized as a potential protein misfolding disease, AD features the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain, contributing significantly to its pathology.

Amyloid Beta and Amyloid Precursor Protein

Amyloid beta, or Aβ, is a short peptide and an abnormal proteolytic byproduct of the amyloid precursor protein (APP). While the precise function of APP is not fully elucidated, it is believed to play a role in neuronal development and synaptic formation. The processing and degradation of APP involve a proteolytic complex, including presenilins, which are crucial for the generation of Aβ.

In its monomeric form, amyloid beta is soluble, featuring regions of beta sheet and polyproline II helix secondary structures in solution, though predominantly adopting an alpha helical structure in membranes. Upon reaching high concentrations, Aβ undergoes a significant conformational shift to a beta sheet-rich tertiary structure, aggregating into Amyloid fibrils that form extracellular deposits. These deposits manifest as senile or neuritic plaques, diffuse plaques, and sometimes within the walls of cerebral vessels in a condition known as amyloid angiopathy or congophilic angiopathy.

Tauopathy and Tau Protein Aggregation

AD is also classified as a tauopathy, characterized by the abnormal aggregation of tau protein, a microtubule-associated protein expressed in neurons. Tau's primary function is to stabilize microtubules in the cell cytoskeleton. However, AD is marked by the accumulation of hyperphosphorylated tau as Paired helical filaments, which aggregate into Neurofibrillary tangles inside neuron cell bodies and as dystrophic neurites around amyloid plaques. The assembly process of these filaments remains poorly understood, though recent research suggests that depletion of a prolyl isomerase in the parvulin family may accelerate abnormal tau accumulation.

Neuroinflammation in Alzheimer's Disease

Neuroinflammation plays a critical role in the progression of AD, with significant pathological and clinical evidence pointing to immunological changes associated with the disease. This includes increased concentrations of pro-inflammatory cytokines in the blood and Cerebrospinal fluid. The causal relationship between these immunological changes and AD is still under investigation, but brain inflammation, including enhanced reactivity of resident microglia towards amyloid deposits, is implicated in the disease's pathogenesis and progression.

Conclusion

The biochemistry of Alzheimer's Disease involves complex interactions between amyloid beta accumulation, tau protein aggregation, and neuroinflammation, leading to the characteristic symptoms and pathology of AD. Continued research is essential for unraveling the precise biochemical mechanisms underlying AD, which could pave the way for novel therapeutic strategies.