Alzheimer’s and Parkinson’s Disease: a gut feeling that we’re looking in the wrong places
By Laura Brown
Despite researchers’ best efforts, a definite cure has yet to be found for either Parkinson’s or Alzheimer’s disease.
Over the last decade, the brain has been the focal point for the origin of these diseases, but scientists are now turning their attention to elsewhere in the body for possible trigger sites and thus targets for novel therapies. Does the gut and its diverse microbiota hold any clues?
Parkinson’s disease (PD) and Alzheimer’s disease (AD) are classified as two distinctly different diseases, but there are certain similarities between them. The most common symptom of PD is the tremor caused by both changes in the basal ganglia circuitry and de-regulated dopamine neurotransmission within the brain. While for AD, memory impairment is the most common symptom. There is often a reciprocal relationship between the two diseases; people with PD are initially diagnosed with movement and co-ordination problems and then, at advanced stages, memory and other cognitive functions deteriorate. Conversely, AD patients are initially diagnosed with memory problems but at advanced stages Parkinsonian symptoms develop.
There is growing awareness of the ‘gut-brain axis (GBA)’, a bidirectional system that allows gut microbes to communicate with the brain and vice versa. Sometimes referred to as ‘the second brain’, Microbiota are a collective of bacteria, viruses, fungi and other organisms that live specifically in the digestive tract. The old view that ‘gut microbiota did us no harm and were of little benefit’ is beginning to change dramatically. One of the common modes of communication between the gut and the brain occurs via the sympathetic and parasympathic nerves. For example, the vagus nerve provides parasympathetic control of basic intestinal functions, innervating areas such as the stomach, small intestine, appendix and distal colon. It has become evident that microbes in the gut are known to contribute to the development of the nervous system, alter behaviour, brain physiology and neurochemistry. Imbalances in the microbial community within the intestine are thought to underlie diseases such as colorectal cancer, inflammatory bowel disease along with neurological disorders such as PD, AD, multiple sclerosis and autism. Reciprocally, perturbations in behaviour, e.g.prolonged periods of stress, are known to alter the composition of the gut microbiota, hence reinforcing the bidirectional relationship.
One of the key neuropathological hallmarks of AD is the high prevalence of a toxic protein fragment called β-amyloid. In a healthy person, proteolysis of amyloid precursor protein (APP) forms β-amyloid, but mutated versions of APP lead to an accumulation of toxic soluble clusters of β-amyloid that are thought to cause synaptic dysfunction and nerve cell death. Ultimately triggering diseases such as dementia. A recent study showed a link between A-β cluster generation and the composition of bacteria in the gut. The authors generated a germ-free (raised in the absence of microbiota) mouse model containing mutated amyloid precursor protein (GF-APP) and found that the levels of A-β pathology were drastically lower compared to a genetically identical mouse model raised in the presence of microbiota (APP). This observation was reinforced through colonization experiments which found that GF-APP mice supplied with microbiota harvested from APP mice displayed an increased number of A-β clusters, whilst GF-APP mice supplied with microbiota from WT mice did not increase the number of A-β clusters. Despite this evidence showing a direct causal link between gut bacteria and β-amyloid generation, it needs to be taken with a degree of cautiousness as AD is now considered a multifactorial disease and is not solely linked to β-amyloid.
Proper brain development and function is linked to an intact blood brain barrier (BBB), which acts as a gatekeeper controlling the passage and exchange of molecules and nutrients between the circulatory system and the central nervous system (CNS). Microbiota are known to influence the integrity of the BBB. Gut microbiota are composed of roughly 50%-70% gram negative bacteria such as E.coli and a major component of the cell wall of these bacteria is a large molecule called lipopolysaccharide (LPS). In healthy people, LPS is blocked from the bloodstream by tight junctions that exist between the intestinal epithelial cells, but when these tight junctions are compromised, this leads to increased permeability of substances in the intestine and LPS can enter the bloodstream and cause inflammation. Plasma levels of LPS in patients with AD are known to be three times higher than healthy controls. LPS is thought to play a role in A-b accumulation and AD progression, since injecting LPS into mice alters the BBB transport of Ab by increasing blood-to-brain influx and decreasing brain-to-blood efflux, albeit indirectly.
Imbalances in intestinal microbiota have also been linked with PD. Although common symptoms of PD predominately include motor impairments such as tremor, non-motor symptoms including loss of smell and gastrointestinal problems persist in a large percentage of PD patients and normally precede the onset of the motor symptoms by years. Next generation sequencing of bacterial genes from faecal samples of PD patients was compared to closely matched controls and results showed alterations in the prevalence of different types of bacteria. This link was investigated further by transplanting faecal samples from PD patients into mice models of PD raised in a germ-free environment. This study concludes that the mice’s PD symptoms worsen in comparison to mice who received samples from people without PD.
Evidence also suggests that patients with PD have increased intestinal permeability compared to healthy controls. It is thought that bodily infections may act as catalysts, initiating a proinflammatory intestinal response which leads to a shift in intestinal permeability. In turn, this promotes leakage of microbiota and various proteins from the intestine, leading to a systemic immune response within the body. One of these proteins includes α-synuclein, which is believed to originate in the enteric nervous system (gastrointestinal), despite extensive characterisation within neurons of the brain. α-synuclein is one of several highly-enriched proteins that form abnormal aggregates called lewy bodies, a common neuropathological hallmark of PD. α-synuclein leaves the intestine and spreads from the circulation to the brain via the vagus nerve where it causes neuronal damage. This was elegantly demonstrated using fluorescently-labelled recombinant α-synuclein taken from a human PD brain lysate. Upon injection of labelled α-synuclein into the gastrointestinal tract (GI tract) wall of adult rats, it was clearly visualised being transported retrogradely via the vagus nerve from the GI tract to the brain. Understanding the gut microbiome and the influence of the gut-brain axis presents opportunities to develop novel diagnostics and therapeutic interventions which act at an earlier stage than those currently available. This could include identification of biomarkers present in the periphery and drugs that either prevent the spread of PD/AD related proteins to the CNS, or drugs that combat inflammation to prevent systemic pro-inflammation responses. Furthermore, targeting peripheral biomarkers also has the significant advantage that drugs can be administered orally without having to cross the BBB.
06. Jaeger, L et al., (2009). Lipopolysaccharide Alters the Blood-brain Barrier Transport of Amyloid Beta Protein: A Mechanism for Inflammation in the Progression of Alzheimer’s Disease. Brain, Behaviour and Immunity. 23(4), 507-517.