Prevention and treatment of amyloid-associated disorders

Details Prevention and treatment of amyloid-associated disorders Prevention and treatment of amyloid-associated disorders

2000-06-30

2003-07-22

Ulm, John (Department: 1646)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

C435S070300, C435S347000, C435S374000, C424S562000

Reexamination Certificate

active

06596474

ABSTRACT:

FIELD OF THE INVENTION
The invention relates generally to the treatment of neurological diseases and specifically to treatment of neurological diseases involving amyloid plaque formation.
BACKGROUND OF THE INVENTION
A number of important neurological diseases including Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), and prion-mediated diseases are characterized by the deposition of aggregated proteins, referred to as amyloid, in the central nervous system (CNS) (for reviews, see Glenner et al. (1989)
J. Neurol. Sci
. 94:1-28; Haan et al. (1990)
Clin. Neurol. Neurosurg
. 92(4):305-310. These highly insoluble aggregates are composed of nonbranching, fibrillar proteins with the common characteristic of a &bgr;-pleated sheet conformation. In the CNS, amyloid can be present in cerebral and meningeal blood vessels (cerebrovascular deposits) and in brain parenchyma (plaques). Neuropathological studies in human and animal models indicate that cells proximal to amyloid deposits are disturbed in their normal functions (Mandybur (1989)
Acta Neuropathol
. 78:329-331; Kawai et al. (1993) Brain Res. 623:142-6; Martin et al. (1994)
Am. J. Pathol
. 145:1348-1381; Kalaria et al. (1995) Neuroreport 6:477-80; Masliah et al. (1996)
J. Neurosci
. 16:5795-5811). AD studies additionally indicate that amyloid fibrils may actually initiate neurodegeneration (Lendon et al. (1997)
J. Am. Med. Assoc
. 277:825-31; Yankner (1996)
Nat. Med
. 2:850-2; Selkoe (1996)
J. Biol. Chem
. 271:18295-8; Hardy (1997)
Trends Neurosci
. 20:154-9).
AD and CAA share biochemical and neuropathological markers, but differ somewhat in the extent and location of amyloid deposits as well as in the symptoms exhibited by affected individuals. The neurodegenerative process of AD, the most common cause of progressive intellectual failure in aged humans, is characterized by the progressive and irreversible deafferentation of the limbic system, association neocortex, and basal forebrain accompanied by neuritic plaque and tangle formation (for a review see Terry et al. (1994) “Structural alteration in Alzheimer's disease.” In: Alzheimer's disease (Terry et al. eds.), pp. 179-196. Raven Press, New York). Dystrophic neurites, as well as reactive astrocytes and microglia, are associated with these amyloid-associated neurite plaques. Although, the neuritic population in any given plaque is mixed, the plaques generally are composed of spherical neurites that contain synaptic proteins, APP (type I), and fusiform neurites containing cytoskeletal proteins and paired helical filaments (PHF; type II).
CAA patients display various vascular syndromes, of which the most documented is cerebral parenchymal hemorrhage. Cerebral parenchymal hemorrhage is the result of extensive amyloid deposition within cerebral vessels (Hardy (1997)
Trends Neurosci
. 20:154-9; Haan et al. (1990)
Clin. Neurol. Neurosurg
. 92:305-10; Terry et al., supra; Vinters (1987)
Stroke
18:211-24; Itoh et al. (1993)
J. Neurological Sci
. 116:135-41; Yamada et al. (1993)
J. Neurol. Neurosurg. Psychiatry
56:543-7; Greenberg et al. (1993)
Neurology
43:2073-9; Levy et al. (1990) Science 2481124-6). In some familial CAA cases, dementia was noted before the onset of hemorrhages, suggesting the possibility that cerebrovascular amyloid deposits may also interfere with cognitive functions.
The precise mechanisms by which neuritic plaques are formed and the relationship of plaque formation to the AD-associated and CAA-associated neurodegenerative processes are not well-defined. Several factors that increase the likelihood of developing AD have already been identified. The risk of developing AD definitely increases with: (1) age, (2) head injuries, (3) family history of AD or Down syndrome, (4) sex, with a higher prevalence of AD in women, (5) vascular disease, (6) exposure to environmental toxins, (7) infectious processes, or (8) changes in immune function. Recent advances in molecular genetics have suggested that genetic predisposition is one of the most important risk factors in the development of AD. For example, a significant increase in the number of amyloid plaques in AD patients with an apolipoprotein E4 (apoE4) allele has been observed and the results of several genetic studies indicate that the etiology of this neurodegenerative disease is associated with the presence of the apoE4 allele.
In both AD and CAA, the main amyloid component is the amyloid &bgr; protein (A&bgr;). The A&bgr; peptide, which is generated from the amyloid &bgr; precursor protein (APP) by two putative secretases, is present at low levels in the normal CNS and blood. Two major variants, A&bgr;
1-40
and A&bgr;
1-42
, are produced by alternative carboxy-terminal truncation of APP (Selkoe et al.(1988)
Proc. Natl. Acad. Sci
. USA 85:7341-7345; Selkoe, (1993)
Trends Neurosci
16:403-409). A&bgr;
1-42
is the more fibrillogenic and more abundant of the two peptides in amyloid deposits of both AD and CAA. In addition to the amyloid deposits in AD cases described above, most AD cases are also associated with amyloid deposition in the vascular walls (Hardy (1997), supra; Haan et al. (1990), supra; Terry et al., supra; Vinters (1987), supra; Itoh et al. (1993), supra; Yamada et al. (1993), supra; Greenberg et al. (1993), supra; Levy et al. (1990), supra). These vascular lesions are the hallmark of CAA, which can exist in the absence of AD.
Glial cell activation is believed to play an essential pathogenic role in the development of dementia. A source of damage in the AD brain is an altered response triggered by microglial activation, which is associated with amyloid plaques. For example, a correlation between genetic predisposition and the proliferation and activation of microglial cells was obtained in AD primary in vitro microglial cell cultures (Lombardi et al. (1998)
J Neurosci Res
54:539-53). Many studies have shown that microglia secrete both cytokines and cytotoxins and since reactive microglia appears in nearly every type of brain damage, it is likely that their secreted products ultimately help to determine the rate of damaged brain tissue. See e.g., Giulian, et al. (1994)
Neurochem Int
. 25:227-33. Reactive microglia may also contribute to neuronal damage by the generation of free oxygen radicals and nitric oxide (NO), which forms the particularly aggressive peroxynitrites, and by the release of potentially neurotoxic cytokines such as tumor necrosis factor-&agr; (TNF-&agr;) (P. Schubert et al. (1998)
Alzheimer Dis Assoc Disord
., 12 Suppl 2:S21-8).
Prostaglandins and nitric oxide (NO) are among the numerous substances released by activated microglial cells. Cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS), the two key enzymes in prostaglandin and NO synthesis, respectively, are rapidly co-induced in rat neonatal microglial cultures activated by bacterial endotoxin (lipopolysaccharide [LPS]). COX-2 expression appears to be under the negative control of endogenous as well as exogenous NO (Minghetti et al. (1997)
Eur J Neurosci
. 9:934-40). Inhibitors of the inducible form of cyclooxygenase (COX-2) have been examined for the treatment of AD. It is becoming increasingly clear, however, that the products of COX-2 mediate both pro- and anti-inflammatory responses, and that inhibiting all COX-2 products in chronic neuroinflammatory states to reduce neuroinflammation inhibits the anti-inflammatory properties certain COX-2 products. Caggiano, (1998)
J. Neurochemistry
70:2357-68. For example, PGI
2
and PGF
2&agr;
are associated with anti-inflammatory activity, and regulation using COX-2 inhibitors may reduce their anti-inflammatory effects.
Prostaglandin E2 (PGE
2
) is also produced by activated microglial cells, and is known to increase cyclic adenosine monophosphate (cAMP) levels in microglial cells (Minghetti et al., supra). Traditionally, PGE
2
has been considered to be a positive factor in inflammation. More recently, however, PGE
2
has been shown to: 1) protect neurons from cytotoxic injury (Akaike et al. (1994)
Brain Research
, 663:23

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