**4. Conclusion**

*Amyloid Diseases*

have an inflammatory component.

components of these many amyloid diseases.

also present in prion-affected brains and usually are found near activated microglia and prion amyloid plaques [89]. As inflammation progresses, inflammatory cytokines are also detected in prion-containing brains [88], and these are thought to play an important role in behavioral changes and neuronal loss observed in affected mice. And this is yet another example of inflammation being widely present and contributing to pathogenesis in an amyloid disease which was first thought to not

**3. What is in store for the future: Therapies for amyloid diseases**

Most amyloid diseases are still incurable. However, most of them can be managed using palliative care and drugs to decrease symptoms and extend the patients' lives. In AD, efforts are concentrated in decreasing symptoms such as cognitive deficits [90]. Currently, there are five FDA-approved drugs to treat cognitive symptoms associated with AD. These drugs are basically acting on two different neurotransmitter systems in the brain: the cholinergic system and the glutamatergic system [90]. They act by blocking glutamate receptors and inhibiting cholinesterase activity, thus these drugs, when combined, can decrease excitotoxicity induced by an overload of glutamate in the synapse and making acetylcholine more available for a healthy synaptic transmission [90]. While in theory, and as seen in mouse models of AD, these drugs seem effective, in humans they work to certain extent decreasing the symptoms. Although these drugs can temporarily decrease symptoms, they are not able to stop the progression of AD, as they do not address amyloid accumulation [90]. Although great results were seen in mouse models, in AD patients, clinical trial using nonsteroidal anti-inflammatory drugs (NSAID) were unsuccessful to prevent or treat the disease, but these drugs only account for a small part of inflammatory pathways dependent on cyclooxygenases (COX) and have diverse side effects. For PD, treatment using drugs is aimed at enhancing cholinergic and dopaminergic transmissions and hence decreasing motor and gut-related symptoms, such as tremors and constipation [91]. Deep-brain stimulation is a surgical treatment available for PD and can also decrease motor symptoms [91]. Most treatments, as the ones described above, are aimed at treating the consequence of amyloid accumulation rather than treating the amyloid accumulation itself or the inflammatory

For the hATTR diseases, two FDA-approved drugs have been developed to prevent amyloid accumulation in patients: tafamidis, a drug that stabilizes TTR and decreases TTR aggregation and antisense oligonucleotides against TTR, a drug that aims in reducing TTR production in the liver [61, 62]. In structure, tafamidis resembles most NSAID, and hence, it does not have any NSAID activity [92]. Notably, many other NSAID drugs also bind to TTR, stabilizing it [93]. However, many have not been to clinical trials at all or have not been successful in clinical trials because chronic use of NSAIDs is not indicated for patients with liver, renal, and heart problems [94], which are part of the symptoms affecting FAP patients. NSAIDs have also been used for treating other amyloid diseases, such as AD and PD, but again without success [95, 96]. Indeed, many AD and PD patients are older individuals that also possess additional conditions that exclude them from the chronic use of NSAIDs. The use of immunotherapies, especially for AD, has been thought to be an effective approach to treating the disease, but clinical trials have shown that autoimmune meningoencephalitis develops in a significant number of patients undergoing immunotherapy [50]. Usually these treatments aim to use

**48**

Amyloid diseases have been described in humans and animals since the 1800s. This family of diseases has one defining characteristic: the presence of extracellular proteinaceous aggregates (amyloid fibrils or plaques) in tissues and organs. These amyloid fibrils arise from the unfolding of native protein, which vary according to the disease (for example, Aβ peptide in AD). Another common characteristic of amyloid diseases is the installment of inflammation during and after amyloid formation. Amyloid fibrils and tissue damage elicit local and nonlocal immune cell infiltration into tissue and proinflammatory cytokine production. Together, these fuel a vicious cycle that can increase amyloid production, as seen in AA amyloidosis, and create an environment of chronic inflammation. A chronically inflamed tissue, as seen in autoimmune diseases, rapidly loose function and deteriorates. This is especially true for the nervous system, a delicate tissue in which self-repair is almost impossible. As most amyloid diseases affect the CNS, and inflammation is a fundamental component of amyloid disease, studying inflammation in the CNS is imperative to our understanding of how to treat amyloid disease. Many current treatments focus on the consequences of amyloid accumulation and fail to address the basic underlying causes. The use of ASOs brings promise of improvements in amyloid disease therapeutics and fortunately is growing as an important tool used in disease therapy. Recognizing that inflammation plays a significant role in amyloid disease is essential to understand the pathogenesis of amyloidosis and important for developing new targeted treatments in an era of growing demand.
