Chronic Bacterial and Viral Infections in Neurodegenerative and Neurobehavioral Diseases

Garth L. Nicolson, PhD


Lab Med. 2008;39(5):291-299. 

In This Article

Alzheimer's Disease

Alzheimer's disease (AD), the most common cause of dementia, is a collection of brain disorders usually found in aged patients. The disease is characterized by slow, progressive loss of brain function, especially notable by lapses in memory, disorientation, confusion, mood swings, changes in personality, language problems (such as difficulty in finding the right words for everyday objects), loss of behavioral inhibitions, loss of motivation, and paranoia. The prognosis and course of AD varies widely, and the duration of illness can range from a few years to over 20 years. During this time, the parts of the brain that control memory and thinking are among the first affected, followed by other brain changes that ultimately result in brain cell death.[72]

Alzheimer's disease is characterized by distinct neuropathological changes in the brain. Among the most notable are the appearance of plaques and tangles of neurofibrils within brain nerves that affect nerve synapses and nerve-nerve cell communication. Both of these structural alterations involve the deposition of altered amyloid (Aβ) proteins.[73,74] Although the cause of AD is not known with any certainty, the formation of the amyloid plaques and neurofiber tangles may be due to genetic defects and resulting changes in the structure of Aβ proteins, neurotox-icity caused by chemicals or other toxic events, inflammatory responses, oxidative stress and increases in reactive oxygen species, loss of nerve trophic factors important in nerve physiology, and loss of nerve cell transmission.[73,74,75,76,77]

Brain infections in AD have only recently become an important topic.[78,79,80] One pathogen that has attracted considerable attention is C. pneumoniae.[81,82] As mentioned above, this intracellular bacterium has a tropism for neural tissue,[81] and it has been found at high incidence in the brains of AD patients (17 of 19 patients in brain areas of typical AD-related pathology) by PCR and immunohistochemistry methods.[82]Chlamydia pneumoniae has also been found in nerve cells in close proximity to neurofibrillary tangles.[82,83] This microorganism can invade endothelial cells and promote the transmigration of monocytes through human brain endothelial cells into the brain parenchyma.[84] Although C. pneumoniae has been found in the brains of most AD patients studied,[77,81] and this infection results in amyloid beta (Aβ) plaque formation in mice injected with C. pneumoniae,[85] some investigators have not found an association of C. pneumoniae infection with AD using PCR or immunohistochemistry.[86,87]

In addition to C. pneumoniae, evidence has been forthcoming that AD patients also have other bacterial infections, such as B. burgdorferi.[88] This infection has been examined in AD cases by serology, culture, Western blot, and immunofluorenscence;[89,90] however, others could not find evidence of B. burgdorferi in AD patients.[91,92] The presence of intracellular infections, like B. burgdorferi in AD patients, has been hypothesized to be a primary event in the formation of AD amyloid plaques by forming "congophilic cores" that attract amyloid materials.[93] Multiple reports show that AD nerve cells are often positive for B. burgdorferi.[88,89,90,93,94]

In addition to the hypothesis that intracellular microorganisms may provide "cores" for the attraction of amyloid materials, the induction of reactive oxygen species, lipid peroxidation, and the breakdown of the lysosomal membranes releasing lysosomal hydrolases are also thought to be important in amyloid deposition.[94] Although the possibility that infections may be important in AD pathogenesis is attractive, some negative reports where investigators have not confirmed the presence of infections, such as B. burgdorferi, in AD patients, indicate that this is still controversial (reviewed in[91,94]).

Herpes simplex virus infections have also been found in AD, and an interesting relationship has developed between the presence of HSV1 in AD.[95] It had been noted previously that HSV1 but not a related neurotrophic virus, varicella zoster virus, was found often in AD brains and may be linked to patients who have the AD risk factor ApoE e4 allele.[96,97] In AD, HSV1 is thought to be involved in the abnormal aggregation of beta amyloid or Aβ fragments within the brain by reducing the amount of full length amyloid precursor protein and increasing the amount of the Aβ fragment from this precursor.[98] Recently, Wozniak and colleagues[99] showed that HSV1 infection of cultured glial and neuronal cells results in a dramatic increase in the intracellular levels of beta amyloid forms, whereas the levels of native amyloid precursor protein decreased. This is similar to what has been found in mice infected with HSV1, indicating that HSV1 is probably involved directly in the development of senile-associated plaques. Another herpesvirus, HHV6, has also been found in AD patients, but it is thought that this virus is not directly involved in AD pathogenesis, but it may exacerbate the effects of HSV1 in ApoE e4 carriers.[100]

In spite of the evidence that AD has been associated with, for example, C. pneumoniae, HSV1, or other infections, Robinson and colleagues[101] have stressed caution in concluding that infections act as a trigger or cofactor in AD. In particular, there is a paucity of experimental evidence that pathogens can elicit the neuropathological changes and cognitive deficits that characterize AD. They also stress that there is a need for consideration of systemic infections as potential contributors to the pathogenesis of AD.


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